IFI44L

A 2016 study reviewing former publications on type I interferon-stimulated genes in lung infections caused by the respiratory syncytial virus (i.e., RSV) reported that the IFI44L gene was overexpressed in: a) the whole blood, peripheral blood mononuclear cells (i.e., PBMCs), oral mucosa, nasal mucosa, respiratory epithelium, and nasopharyngeal aspirates (i.e., suctions) of patients hospitalized for RSV infections; b) the cord blood of RSV-infected newborn infants; c) several different cultured human immortalized cell lines after being infected with RSV; and d) the lung tissue and whole blood of mice after being infected with RSV.{{cite journal | vauthors = McDonald JU, Kaforou M, Clare S, Hale C, Ivanova M, Huntley D, Dorner M, Wright VJ, Levin M, Martinon-Torres F, Herberg JA, Tregoning JS | title = A Simple Screening Approach To Prioritize Genes for Functional Analysis Identifies a Role for Interferon Regulatory Factor 7 in the Control of Respiratory Syncytial Virus Disease | journal = mSystems | volume = 1 | issue = 3 | pages = | date = 2016 | pmid = 27822537 | pmc = 5069771 | doi = 10.1128/mSystems.00051-16 | url = }} A subsequent study found that: a) RSV stimulated cultured A549 cells (i.e., immortalized cells derived from human adenocarcinoma lung cells) to increase their IFI44L mRNA levels; b) intranasal injection of RSV into BALB/c mice increased the levels of IFI44L mRNA in their PBMCs; c) intranasal injection of RSV into C57BL/6N mice (i.e., mice that lack the IFI44L gene) developed greater weight losses and higher levels of RSV mRNA in their lung tissue than C57BL/6 mice (i.e., mice that have the IFI44L gene); d) cultured A549 cells that had their IFI44R gene disabled using gene knockout methods proliferated more rapidly than A549 cells that did not have this disablement; e) forced overexpression of the IFI44L gene in cultured 549 cells decreased their rate of proliferation; f) cultured A549 cells made to overexpress IFI44L mRNA had a lower percentage of cells that could be infected with RSV and a lower number of RSV recovered from their cultures; g) cultures of A549 cells made to express low levels of IFI44L mRNA and infected with RSV developed 2-fold higher levels of RSV than cultures of RSV-infected cells that expressed normal levels of IFI44L mRNA; and h) following intranasal inoculation with RSV, C57BL/6N mice, which lack functional IFI44L and IIFI44 genes, developed a far more severe RSV infection that mice lacking only one of these genes. The study also reported that 12 infants with severe RSV infections who were admitted to a hospital had significantly lower levels of IFI44L and IFI44 mRNA in their PBMCs than 6 infants with mild RSV who were admitted to this hospital. The study concluded that: a) high expression of the IFI44L gene reduces the growth of RSV and RSV-infected cells in cultured human lung cells and in mice; b) the increased expression of the IFI44L gene in infants infected with RSV is associated with significantly less severe disease than infants who expressed lower levels of the IFI44L gene; c) further studies are needed to confirm that overexpression of the IFI44L gene is associated with less severe RSV infections in infants infected with RSV, to determine if the IFI44L gene is overexpressed in children and adults with less severe RSV, to determine if the levels of this gene's expression would be useful for predicting the severity of RSV infection, and to determine if methods that promote overexpression of the IFI44L gene would be useful in treating RSV infections.

In contrast to the findings in RSV infections, cultured A549 cells infected with the Influenza A virus or the lymphocytic choriomeningitis virus and cultured Huh7 human liver cancer cells infected with the human coronavirus 229E: a) had far higher IFI44L mRNA levels than mock-infected cells; b) had reduced numbers of these viruses in their respective cells when their IFI44L genes were knocked out (i.e., deleted or inactivated); and c) knocking out the IFI44L gene also suppressed the expression of two interferon-induced proteins, IFIT2 and IFN-λ1. (IFIT2{{cite journal | vauthors = Wu YY, Xing J, Li XF, Yang YL, Shao H, Li J | title = Roles of interferon induced protein with tetratricopeptide repeats (IFIT) family in autoimmune disease | journal = Autoimmunity Reviews | volume = 22 | issue = 11 | pages = 103453 | date = November 2023 | pmid = 37741527 | doi = 10.1016/j.autrev.2023.103453 | url = }} and IFN-λ1{{cite journal | vauthors = Franco JH, Chattopadhyay S, Pan ZK | title = How Different Pathologies Are Affected by IFIT Expression | journal = Viruses | volume = 15 | issue = 2 | date = January 2023 | page = 342 | pmid = 36851555 | pmc = 9963598 | doi = 10.3390/v15020342 | doi-access = free | url = }} inhibit the growth and replication of various viruses.) These results indicate that the IFI44L protein promotes the proliferation of these three viruses in their respective cultured cells and appears to do so by inhibiting them from making two inhibitors of viral growth/proliferation, i.e., the type I interferon-stimulated IFIT2 protein and type III interferon-simulated IFN-λ1 protein. A study of 32 patients who had SARS-CoV-2, (a form of coronavirus that causes COVID-19) for 5 to 17 weeks reported that 15 patients with symptomatic covid-19 disease had significantly higher peripheral blood cell levels of IFI44L mRNA than 17 patients who did not develop symptoms of this infection. The study suggested that high blood cell levels IFI44L mRNA (and therefore IFI44L protein) contributes to the development of symptoms in patients with COVID-19 infections.{{cite journal | vauthors = Sfikakis PP, Verrou KM, Ampatziadis-Michailidis G, Tsitsilonis O, Paraskevis D, Kastritis E, Lianidou E, Moutsatsou P, Terpos E, Trougakos I, Chini V, Manoloukos M, Moulos P, Pavlopoulos GA, Kollias G, Hatzis P, Dimopoulos MA | title = Blood Transcriptomes of Anti-SARS-CoV-2 Antibody-Positive Healthy Individuals Who Experienced Asymptomatic Versus Clinical Infection | journal = Frontiers in Immunology | volume = 12 | issue = | pages = 746203 | date = 2021 | pmid = 34675930 | pmc = 8523987 | doi = 10.3389/fimmu.2021.746203 | doi-access = free | url = }} An epigenome-wide association study on the DNA methylation of genes in individuals with Covid-19 reported that CpG sites (i.e., cytosine-phosphate-guanine sites) in a promotor (identified as the cg03607951 site ) of the IFI44L gene in the blood cells of 109 patients with Covid-19 had significantly lower levels of cytosine methylation than 71 non-infected individuals. Low levels of cytosine methylation in a gene's CPG promotor are usually associated with increases in the expression of this promotor's gene.{{cite journal | vauthors = Zhang L, Wang R, Xie Z | title = The roles of DNA methylation on the promotor of the Epstein-Barr virus (EBV) gene and the genome in patients with EBV-associated diseases | journal = Applied Microbiology and Biotechnology | volume = 106 | issue = 12 | pages = 4413–4426 | date = June 2022 | pmid = 35763069 | pmc = 9259528 | doi = 10.1007/s00253-022-12029-3 | url = }} This study supported the conclusion that high levels of IFI44L promote the development of symptomatic Covid-19 in humans.

Hepatitis B virus (i.e., HBV) causes a form of chronic hepatitis that may lead to cirrhosis, cancer, and failure of the liver. HBV is a DNA virus that infects hepatocytes (i.e., liver cells) as a virion particle with its genetic material in the form of relaxed, circular DNA (i.e., rcDNA).{{cite journal | vauthors = Nosaka T, Naito T, Murata Y, Matsuda H, Ohtani M, Hiramatsu K, Nishizawa T, Okamoto H, Nakamoto Y | title = Regulatory function of interferon-inducible 44-like for hepatitis B virus covalently closed circular DNA in primary human hepatocytes | journal = Hepatology Research| volume = 52 | issue = 2 | pages = 141–152 | date = February 2022 | pmid = 34697871 | doi = 10.1111/hepr.13722 | url = }} Once inside the hepatocyte, it replicates by converting its rcDNA to covalently closed circular DNA (i.e., cccDNA: see rcDNA and cccDNA). cccDNA forms the proteins that transcribe the HBV DNA into mRNA and translate this mRNA into proteins that make HBV virions which leave the cell to infect other hepatocytes.{{cite journal | vauthors = Testoni B, Scholtès C, Plissonnier ML, Paturel A, Berby F, Facchetti F, Villeret F, Degasperi E, Scott B, Hamilton A, Heil M, Lampertico P, Levrero M, Zoulim F | title = Quantification of circulating HBV RNA expressed from intrahepatic cccDNA in untreated and NUC treated patients with chronic hepatitis B | journal = Gut | volume = 73 | issue = 4 | pages = 659–667 | date = March 2024 | pmid = 37879886 | pmc = 10958289 | doi = 10.1136/gutjnl-2023-330644 | url = }} As of 2024, there were 7 drugs licensed to treat chronic HBV hepatitis B infection in the United States{{cite web|url=https://www.hepb.org/treatment-and-management/treatment/approved-drugs-for-adults/|title=Approved Hepatitis B Drugs for Adults (United States)|year=2024}}(see treatment of chronic HBV hepatitis). These drugs suppress the replication of HBV but do not remove all of the HBV cccDNA, i.e., these drugs as well as various experimental treatments do not completely eliminate or inactivate cccDNA and therefore do not cure HBV-induced hepatitis.{{cite journal | vauthors = Nguyen MH, Wong G, Gane E, Kao JH, Dusheiko G | title = Hepatitis B Virus: Advances in Prevention, Diagnosis, and Therapy | journal = Clinical Microbiology Reviews | volume = 33 | issue = 2 | pages = | date = March 2020 | pmid = 32102898 | pmc = 7048015 | doi = 10.1128/CMR.00046-19 | url = }}{{cite journal | vauthors = Schlaak JF | title = Current Therapy of Chronic Viral Hepatitis B, C and D | journal = Journal of Personalized Medicine | volume = 13 | issue = 6 | date = June 2023 | page = 964 | pmid = 37373953 | pmc = 10305460 | doi = 10.3390/jpm13060964 | doi-access = free | url = }} A study quantified the replication of HBV virions made by cultured Hep G2 human hepatocellular carcinoma cells by: a) infecting cultured Hep G2 cells with a form of HBV that causes severe liver damage in humans; b) adding the extracellular media of these Hep G2 cultures to cultures of PXB cells (i.e., human hepatocytes isolated from humanized PBX-mice); c) treating the cultured PXB cells with IFN-α, IFN-γ, or interferon-free culture medium on days 4, 8, 13, 18, and 23; and d) measuring the effects of these treatments on various indicators of HBV production. The culture media from untreated Hep G2 cells caused the PXB cells to develop progressively increasing levels of HBV virions and the HBsAg surface antigen of these virions over this 23 day period while the PXB cells, which were examined at day 23, developed increased levels of cccDNA, HBsAg, and HBV virions. In contrast, PXB cells treated with IFN-α or IFN-γ had increased levels of IFI44L mRNA and decreased levels of cccDNA, HBsAg and HBV virions while their media had decreased levels of HBV virions and HBsAg surface antigen. PXB cells that had their IFI44L partially knocked down showed far less of these IFN-α- and IFN-γ-induced changes. Thus, activation of the IFI44L gene appeared to suppress the intracellular replication of HBV and support studies to determine if it can be used to cure HBV infections in animal models and humans.

Children less than 2 years old have high rates (average 6/year) of respiratory tract infections (RTIs) that are mostly caused by viruses and often complicated by otitis media (i.e., middle ear infections) caused by viruses or bacteria. Two studies conducted in Finland, the STEPS Study and FinnBrain Birth Cohort Study, reported that the rates and severities of these RTIs differed in children who carried different single nucleotide polymorphism (i.e., SNIP) IFI44L gene variants. (A SNIP gene is a gene that has two different nucleic acid sequences only one of which is carried by an individual.) These IFI44L variants were:{{cite journal | vauthors = Lempainen J, Korhonen LS, Kantojärvi K, Heinonen S, Toivonen L, Räty P, Ramilo O, Mejias A, Laine AP, Vuorinen T, Waris M, Karlsson L, Karlsson H, Paunio T, Peltola V | title = Associations Between IFI44L Gene Variants and Rates of Respiratory Tract Infections During Early Childhood | journal = The Journal of Infectious Diseases | volume = 223 | issue = 1 | pages = 157–165 | date = January 2021 | pmid = 32561935 | doi = 10.1093/infdis/jiaa341 | url = }} a) rs273259, a missense gene variant (i.e. a variant that causes a change in the amino acid sequence of the protein) in exon 2 of the IFI44L gene that has a guanine rather than adenine nucleotide thereby coding for a histidine rather than arginine at position 73 in the IFI44L protein (change notated as His73Arg);{{cite journal | vauthors = Haralambieva IH, Ovsyannikova IG, Kennedy RB, Larrabee BR, Zimmermann MT, Grill DE, Schaid DJ, Poland GA | title = Genome-wide associations of CD46 and IFI44L genetic variants with neutralizing antibody response to measles vaccine | journal = Human Genetics | volume = 136 | issue = 4 | pages = 421–435 | date = April 2017 | pmid = 28289848 | pmc = 5433429 | doi = 10.1007/s00439-017-1768-9 | url = }} and b) rs1333969 which has an intronic change (i.e., a change that does not alter the ammino acid sequence of the IFI44L protein) in the IFI44L gene.https://www.ncbi.nlm.nih.gov/snp/rs1333969/ In the STEPS study, children with the rs273259 or rs1333969 forms of the IFI44L gene had a decreased number of days they had RTI symptoms and a decreased rate of developing acute otitis media from birth to 2 years of age. In the FinnBrain Birth Cohort Study, children with the rs273259 and rs1333969 variants of this gene had a decreased rate of developing RTIs during their first year of life. Children with either variant had significant decreases in the expression of the IFI44L protein. The study concluded that these variant IFI44L genes reduced the expression or their IFI44L proteins and these reductions were associated with decreased rates of developing RTIs and acute otitis media.

Studies have shown that the IFI44L mRNA in the peripheral blood or certain peripheral blood cells is elevated in: a) 11 febrile children aged 1 to 6.4 years old with various viral infections;{{cite journal | vauthors = Gómez-Carballa A, Cebey-López M, Pardo-Seco J, Barral-Arca R, Rivero-Calle I, Pischedda S, Currás-Tuala MJ, Gómez-Rial J, Barros F, Martinón-Torres F, Salas A | title = A qPCR expression assay of IFI44L gene differentiates viral from bacterial infections in febrile children | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 11780 | date = August 2019 | pmid = 31409879 | pmc = 6692396 | doi = 10.1038/s41598-019-48162-9 | bibcode = 2019NatSR...911780G | url = }} b) 92 children (median age 1.5 years) with various viral infections;{{cite journal | vauthors = Herberg JA, Kaforou M, Wright VJ, Shailes H, Eleftherohorinou H, Hoggart CJ, Cebey-López M, Carter MJ, Janes VA, Gormley S, Shimizu C, Tremoulet AH, Barendregt AM, Salas A, Kanegaye J, Pollard AJ, Faust SN, Patel S, Kuijpers T, Martinón-Torres F, Burns JC, Coin LJ, Levin M | title = Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children | journal = JAMA | volume = 316 | issue = 8 | pages = 835–45 | date = 2016 | pmid = 27552617 | pmc = 5997174 | doi = 10.1001/jama.2016.11236 | url = }} and c) 212 adult patients with an acute febrile illness caused by various viruses.{{cite journal | vauthors = Xu N, Hao F, Dong X, Yao Y, Guan Y, Yang L, Chen F, Zheng F, Li Q, Liu W, Zhao C, Li W, Palavecino E, Wang W, Wang G | title = A two-transcript biomarker of host classifier genes for discrimination of bacterial from viral infection in acute febrile illness: a multicentre discovery and validation study | journal = The Lancet. Digital Health | volume = 3 | issue = 8 | pages = e507–e516 | date = August 2021 | pmid = 34325854 | doi = 10.1016/S2589-7500(21)00102-3 | url = | doi-access = free }} These studies concluded that the peripheral blood and certain peripheral blood cells develop increases in IFI44L mRNA in patients with a wide range of viral infections and support further studies to show that measuring blood IFI44L mRNA levels are useful for distinguishing viral from bacterial infections in infants, children, and adults (the section "Distinguishing between viral from bacterial infections" reports on studies finding that many bacterial infections are not associated with significant increases in the expression of the IFI44L gene).{{cite journal | vauthors = Tian S, Deng J, Huang W, Liu L, Chen Y, Jiang Y, Liu G | title = FAM89A and IFI44L for distinguishing between viral and bacterial infections in children with febrile illness | journal = Pediatric Investigation | volume = 5 | issue = 3 | pages = 195–202 | date = September 2021 | pmid = 34589675 | pmc = 8458721 | doi = 10.1002/ped4.12295 | url = }}

A study testing the function of the IFI44L gene in Mycobacterium tuberculosis (which causes tuberculosis, i.e., TB) reported that cultures of a macrophage cell line derived from the THP-1 human monocytic cell line developed higher IFI44L mRNA levels and lower levels of four inflammation-promoting cytokines, (i.e., CCL4, CXCL10, CXCL11, and IL18) after being infected with the H37Rv strain of mycobacterium tuberculosis. The survival of these mycobacteria was greatly increased in macrophages that had their IFI44L gene knocked out. In addition, the levels of IFI44L mRNA rose while the survival of H37Rv mycobacteria and levels of the cited inflammatory cytokines fell in macrophages pretreated with rifampicin, a mycobacterium-killing drug. Furthermore, rifampicin-based anti-tuberculosis drug treatment of 10 patients who had the cutaneous form of TB for 1 to 6 months caused decreases in their skin lesions and decreases in their PMBCs levels of IFI44L mRNA, IFI44L protein, and the cited cytokines.{{cite journal | vauthors = Jiang H, Tsang L, Wang H, Liu C | title = IFI44L as a Forward Regulator Enhancing Host Antituberculosis Responses | journal = Journal of Immunology Research | volume = 2021 | issue = | pages = 5599408 | date = 2021 | pmid = 34722780 | pmc = 8550841 | doi = 10.1155/2021/5599408 | doi-access = free | url = }} Other studies have reported that: 176 patients with TB had higher levels of IFI44L mRNA in their peripheral blood than 215 heathy individuals;{{cite journal | vauthors = Sambarey A, Devaprasad A, Mohan A, Ahmed A, Nayak S, Swaminathan S, D'Souza G, Jesuraj A, Dhar C, Babu S, Vyakarnam A, Chandra N | title = Unbiased Identification of Blood-based Biomarkers for Pulmonary Tuberculosis by Modeling and Mining Molecular Interaction Networks | journal = eBioMedicine | volume = 15 | issue = | pages = 112–126 | date = February 2017 | pmid = 28065665 | pmc = 5233809 | doi = 10.1016/j.ebiom.2016.12.009 | url = }} 195 patients with TB had higher levels of IFI44L mRNA in their peripheral blood than 210 healthy controls;{{cite journal | vauthors = Shi T, Huang L, Zhou Y, Tian J | title = Role of GBP1 in innate immunity and potential as a tuberculosis biomarker | journal = Scientific Reports | volume = 12 | issue = 1 | pages = 11097 | date = June 2022 | pmid = 35773466 | pmc = 9247026 | doi = 10.1038/s41598-022-15482-2 | bibcode = 2022NatSR..1211097S | url = }} 84 patients with TB had higher levels of IFI44L mRNA in their peripheral blood than 81 healthy individuals;{{cite journal | vauthors = Deng S, Shen S, Liu K, El-Ashram S, Alouffi A, Cenci-Goga BT, Ye G, Cao C, Luo T, Zhang H, Li W, Li S, Zhang W, Wu J, Chen C | title = Integrated bioinformatic analyses investigate macrophage-M1-related biomarkers and tuberculosis therapeutic drugs | journal = Frontiers in Genetics | volume = 14 | issue = | pages = 1041892 | date = 2023 | pmid = 36845395 | pmc = 9945105 | doi = 10.3389/fgene.2023.1041892 | doi-access = free | url = }} and 20 patients with TB had higher levels of IFI44L mRNA in the peripheral blood than 19 healthy patient.{{cite journal | vauthors = Huang T, He J, Zhou X, Pan H, He F, Du A, Yu B, Jiang N, Li X, Yuan K, Wang Z | title = Discovering common pathogenetic processes between COVID-19 and tuberculosis by bioinformatics and system biology approach | journal = Frontiers in Cellular and Infection Microbiology | volume = 13 | issue = | pages = 1280223 | date = 2023 | pmid = 38162574 | pmc = 10757339 | doi = 10.3389/fcimb.2023.1280223 | doi-access = free | url = }} These studies indicate that the IFI44L gene is overexpressed in patients with tuberculosis, suggest that the IFI44L protein clears mycobacterium from cultured macrophages and mycobacterial skin lesions at least in part by promoting the production of pro-inflammatory cytokines, and support future studies to determine if the IFI44L gene is a target for therapeutic strategies (e.g., increasing its activation) to treat Mycobacterium tuberculosis and a useful biomarker for determining the effectiveness of antituberculosis therapy.

Studies suggest that, except for Mycobacterium tuberculosis, many types of bacterial infections are not associated with appreciable activation of the IFI44L gene as defined by rises in IFI44l mRNA, at lease as compared to viral infections levels. However, these studies often did not define the types of bacteria examined and included only a small number of bacterial types (see next section on "Distinguishing between viral and bacterial infections).

A study reported that the peripheral blood levels of IFI44L mRNA were higher and Fam89A mRNA were lower in 47 young children with proven viral compared to 33 patients with proven bacterial infections. This study used a disease risk score (i.e., DRC, a number summarizing a person's risk of developing a particular disease) which it defined as the sum of the levels of these two mRNAs. This DRC clearly distinguished viral from bacterial infections in these children. A second study examined 30 children 0.6–15 years old who, while being treated with chemotherapy for cancer, presented with neutropenia plus clinical evidence of having a viral or bacterial infection. The study used a DRC it defined by subtracting the normalized log2 expression value of IFI44L from the normalized log2 expression value of FAM89A. (Normalized Log2 expression values convert mRNA levels into numbers more easily compared and analyzed.{{cite journal | vauthors = Fundel K, Haag J, Gebhard PM, Zimmer R, Aigner T | title = Normalization strategies for mRNA expression data in cartilage research | journal = Osteoarthritis and Cartilage | volume = 16 | issue = 8 | pages = 947–55 | date = August 2008 | pmid = 18258458 | doi = 10.1016/j.joca.2007.12.007 | url = }} see binary logarithm). In this study, a higher DRC score correctly indicated a bacterial infection in 17 patients and a lower DRC correctly indicated a viral infection in 13 children.{{cite journal | vauthors = Aasa J, Tiselius E, Sinha I, Edman G, Wahlund M, Hedengren SS, Nilsson A, Berggren A | title = The Applicability of a 2-Transcript Signature to Identify Bacterial Infections in Children with Febrile Neutropenia | journal = Children | volume = 10 | issue = 6 | date = May 2023 | page = 966 | pmid = 37371198 | pmc = 10297134 | doi = 10.3390/children10060966 | doi-access = free | url = }} A third study using this DRC found that 89 neonates and infants less than 60 days old who had a high DRC were correctly diagnosed as having a bacterial infection and 111 neonates and infants less than 60 days old who had a low DRC correctly diagnosed a viral infection with a high degree accuracy (95.7%).{{cite journal | vauthors = Kaforou M, Herberg JA, Wright VJ, Coin LJ, Levin M | title = Diagnosis of Bacterial Infection Using a 2-Transcript Host RNA Signature in Febrile Infants 60 Days or Younger | journal = JAMA | volume = 317 | issue = 15 | pages = 1577–1578 | date = April 2017 | pmid = 28418473 | doi = 10.1001/jama.2017.1365 | hdl = 10044/1/64273 | url = | hdl-access = free }} A fourth study on children less than 14 years of age with a bacterial (39 patients) or viral (59 patients) febrile illness were correctly diagnosed using the latter DRS with an accuracy of 82.5%. Taken together, these studies suggest that the cited DRC measurements of IFI44L and Fam89A mRNA levels in the blood of children, infants, and neonates with the signs and symptoms of an acute infection can significantly contribute to determining whether an infection is bacterial or viral in origin.

Squamous-cell carcinomas of the head and neck are cancers derived from the mucosal epithelium in the oral cavity, pharynx (which includes the hypopharynx), or larynx. They consist mostly of and therefore are collectively termed head and neck squamous cell carcinomas, i.e., HNSCCs.{{cite journal | vauthors = Johnson DE, Burtness B, Leemans CR, Lui VW, Bauman JE, Grandis JR | title = Head and neck squamous cell carcinoma | journal = Nature Reviews. Disease Primers | volume = 6 | issue = 1 | pages = 92 | date = November 2020 | pmid = 33243986 | pmc = 7944998 | doi = 10.1038/s41572-020-00224-3 | url = }} A study reported that the cells in patient HNSCCs had significantly higher levels of IFI44L protein (as defined using antibodies directed at this protein) than cells in nearby normal head and neck epithelium tissues. Similarly, three immortalized human cell lines, FaDu cells (i.e., cells derived from a human squamous cell carcinoma of the hypopharynx{{cite journal | vauthors = Rangan SR | title = A new human cell line (FaDu) from a hypopharyngeal carcinoma | journal = Cancer | volume = 29 | issue = 1 | pages = 117–21 | date = January 1972 | pmid = 4332311 | doi = 10.1002/1097-0142(197201)29:1<117::aid-cncr2820290119>3.0.co;2-r | url = }}), HSC‐3 cells (i.e., cells derived from a human tongue cancer{{cite journal | vauthors = Dubeykovskaya ZA, Tu NH, Garcia PD, Schmidt BL, Albertson DG | title = Oral Cancer Cells Release Vesicles that Cause Pain | journal = Advanced Biology | volume = 6 | issue = 9 | pages = e2200073 | date = September 2022 | pmid = 35802912 | pmc = 9474716 | doi = 10.1002/adbi.202200073 | url = }}), and SAS cells (i.e., cells derived from a human tongue squamous cell carcinoma{{cite journal | vauthors = Chen WF, Tsai SC, Zhang YH, Chang HM, Wu WJ, Su JH, Wu BN, Chen CY, Lin MY, Chen HL, Lee CH | title = Rhopaloic acid A triggers mitochondria damage-induced apoptosis in oral cancer by JNK/BNIP3/Nix-mediated mitophagy | journal = Phytomedicine | volume = 132 | issue = | pages = 155855 | date = September 2024 | pmid = 39043083 | doi = 10.1016/j.phymed.2024.155855 | url = }}) had higher IFI44L protein levels than HOK cells (i.e., cells derived from human non-cancerous oral keratinocytes). Long-chain-fatty-acid—CoA ligase 4, also termed long‐chain acyl‐CoA synthetase 4 or ACSL4, is an enzyme that converts fatty acids to their fatty acyl-CoA esters. It is also implicated in increasing the invasiveness, migration, and survival of cultured colon, prostate, breast, lung, and brain cancer immortalized cell lines.{{cite journal | vauthors = Belkaid A, Ouellette RJ, Surette ME | title = 17β-estradiol-induced ACSL4 protein expression promotes an invasive phenotype in estrogen receptor positive mammary carcinoma cells | journal = Carcinogenesis | volume = 38 | issue = 4 | pages = 402–410 | date = April 2017 | pmid = 28334272 | doi = 10.1093/carcin/bgx020 | url = }}{{cite journal | vauthors = Chen J, Ding C, Chen Y, Hu W, Yu C, Peng C, Feng X, Cheng Q, Wu W, Lu Y, Xie H, Zhou L, Wu J, Zheng S | title = ACSL4 reprograms fatty acid metabolism in hepatocellular carcinoma via c-Myc/SREBP1 pathway | journal = Cancer Letters | volume = 502 | issue = | pages = 154–165 | date = April 2021 | pmid = 33340617 | doi = 10.1016/j.canlet.2020.12.019 | url = }} Similar to IFI44L, ACSL4 protein levels were higher in patient's HNSCC tumor tissues than their nearby normal head and neck epithelial tissues. Furthermore, patients with HNSCC tumors that expressed higher levels of ACSL4 protein had significantly shorter survival times than patients with lower ACSL4 protein levels. Finally, cultured OECM‐1 (a human oral squamous carcinoma cell line{{cite journal | vauthors = Covarrubias AA, Reyna-Jeldes M, Pedroso-Santana S, Marín S, Madero-Mendoza C, Demergasso C, Coddou C | title = Arsenic Nanoparticles Trigger Apoptosis via Anoikis Induction in OECM-1 Cells | journal = International Journal of Molecular Sciences | volume = 25 | issue = 12 | date = June 2024 | page = 6723 | pmid = 38928430 | pmc = 11204275 | doi = 10.3390/ijms25126723 | doi-access = free | url = }}), SAS, and HSC‐3 cells that had their ACSL4 protein levels reduced using short hairpin RNAs showed significantly decreased levels of IFI44L as well as their rates of proliferation, migration, and invasiveness than the same cell lines that were treated with inactive short hairpin RNAs. Thus, high IFI44L protein levels promote the malignant behavior of cultured HNSCC tumor cells; high levels of ACSL4 and IFI44L are associated with increased aggressiveness of HNSCCs and shorter survival times in patients with HNSCCs; these actions of high ACSL4 levels may be caused at least in part by its increasing IFI44L levels; and IFI44L and ACSL4 may prove useful parameters of disease severity as well as potential therapeutic targets for treating HNSCC. In two other studies, IFI44L mRNA levels were found to be higher in patient nasopharyngeal carcinomas than normal nasopharyngeal tissues based on a large number of samples in the Gene Expression Omnibus{{cite journal | vauthors = Wu X, Lin L, Zhou F, Yu S, Chen M, Wang S | title = The Highly Expressed IFIT1 in Nasopharyngeal Carcinoma Enhances Proliferation, Migration, and Invasion of Nasopharyngeal Carcinoma Cells | journal = Molecular Biotechnology | volume = 64 | issue = 6 | pages = 621–636 | date = June 2022 | pmid = 35038119 | doi = 10.1007/s12033-021-00439-z | url = }} and IFI44L mRNA levels were reported to be significantly higher in 209 patient oral squamous cell carcinomas than normal oral tissues with carcinomas having higher levels of IFI44L mRNA being associated with poorer overall survival rates.{{cite journal | vauthors = Reyimu A, Chen Y, Song X, Zhou W, Dai J, Jiang F | title = Identification of latent biomarkers in connection with progression and prognosis in oral cancer by comprehensive bioinformatics analysis | journal = World Journal of Surgical Oncology | volume = 19 | issue = 1 | pages = 240 | date = August 2021 | pmid = 34384424 | pmc = 8361649 | doi = 10.1186/s12957-021-02360-w | doi-access = free | url = }}

A study reviewing 217 patients with hepatocellular carcinoma in China reported that the levels of IFI44L protein in their carcinomas were significantly lower in patients who had larger tumor sizes, advanced stage disease, disease relapses, and/or shorter survival times. This study also examined cultures of human Hep3B, Hep G2, and PLC hepatocarcinoma cells or the stem cells cells isolated from these hepatocarcinoma Immortalised cell lines.(Stem cells are a small subset of cells in cancers that self-renew, continuously proliferate, form tumors, metastasize, and maintain tumor heterogeneity.{{cite journal | vauthors = Chu X, Tian W, Ning J, Xiao G, Zhou Y, Wang Z, Zhai Z, Tanzhu G, Yang J, Zhou R | title = Cancer stem cells: advances in knowledge and implications for cancer therapy | journal = Signal Transduction and Targeted Therapy | volume = 9 | issue = 1 | pages = 170 | date = July 2024 | pmid = 38965243 | pmc = 11224386 | doi = 10.1038/s41392-024-01851-y | url = }}) These culture cell studies showed that the forced overexpression of IFI44L protein by transfection with a plasmid containing the human IFI44L gene into Hep3B cells, Hep G2 cells, or the stem cells isolated from these two cell lines increased their sensitivity to the lethal effects of doxorubicin; reducing IFI44L protein levels using small interfering RNA restored these cells' resistance to this chemotherapy drug. Finally, depletion of the IFI44L gene in cultures of Hep3B, Hep G2, and PLC cells using a gene knockdown method enhanced their migration and invasiveness as measured by in vitro assays as well as pulmonary metastasis as measured by injecting these cells into 6-8-week-old severe combined immunodeficient mice. These results suggest that the IFI44L gene is a tumor suppressor gene for hepatocellular carcinoma at least in the cited Chinese population and, if confirmed in future studies including those conducted outside of China, would indicate that INI44L protein levels can be used as a predictive biomarker of hepatocellular disease severity and a promising therapeutic target (i.e., by increasing its levels) for treating hepatocellular carcinomas.

A study{{cite journal | vauthors = Zeng Y, Zhang Z, Chen H, Fan J, Yuan W, Li J, Zhou S, Liu W | title = Comprehensive Analysis of Immune Implication and Prognostic Value of IFI44L in Non-Small Cell Lung Cancer | journal = Frontiers in Oncology | volume = 11 | issue = | pages = 798425 | date = 2021 | pmid = 35047409 | pmc = 8761744 | doi = 10.3389/fonc.2021.798425 | doi-access = free | url = }} of two non-small cell lung cancer forms, i.e., lung adenocarinoma (LAD) and lung squamous cell carcinoma (LSC), reported that: a) cell culture assays on the growth, proliferation, and invasiveness of two human lung cancer immortalized cell lines representing LAD and LSC cells, i.e. SPC-A-1 and NCI-H520 cells, respectively, were inhibited by forcing these cells to overexpress the IFI44L gene; b) IFI44L mRNA levels were significantly lower in 497 LAD and 489 LSC patient tissues than in normal lung tissues; c) the levels of IFI44L mRNA in LAD and LSC patient tissues increased with increases in the numbers of inflammation-producing and potentially tumor-suppressing immune cell types in these tissues but decreased with the number of relatively inactive or tumor tolerance-promoting types of immune cells in these tissues; and d) dividing LAD and LSC into high and low scores based on the number and types of immune cells in patient LAD and LSC tissues successfully classified patients into low risk and high risk groups with the low risk group having a longer overall survival rate than patients in the high risk group. These studies indicate that overexpression of the IFI44L gene inhibits the growth of cultured SOC-A-1 (i.e., LAD-like) and NCI-h520 (i.e., LSC-like) forms of non-small cell lung cancer, that treatments which stimulate the IFI44L gene may be therapeutically useful for treating these cancers, and that measurements of the levels of the various immune cell types in these cancers may prove to be useful indicators of these tumors' aggressiveness and patient survivals. A subsequent study{{cite journal | vauthors = Zeng Y, Chen HQ, Zhang Z, Fan J, Li JZ, Zhou SM, Wang N, Yan SP, Cao J, Liu JY, Zhou ZY, Liu WB | title = IFI44L as a novel epigenetic silencing tumor suppressor promotes apoptosis through JAK/STAT1 pathway during lung carcinogenesis | journal = Environmental Pollution (Barking, Essex: 1987) | volume = 319 | issue = | pages = 120943 | date = February 2023 | pmid = 36584854 | doi = 10.1016/j.envpol.2022.120943 | bibcode = 2023EPoll.31920943Z | url = }} found that non-malignant human bronchial epithelial cells (i.e., HBE cells) responded to treatment with a cancer-causing chemical, 3-methylcholanthrene, by significantly decreasing their levels of IFI44L mRNA and protein. This study also showed that: a) compared to normal lung tissue, the levels of IFI44L mRNA and IFI44L protein were low and methylations of the IFI44L gene at three sites (i.e., cg17980508, cg03607951, and cg27315157) were increased in 486 cases of human lung adenocarcinoma; b) expression of the IFI44L gene was decreased in adenocarcinoma tissues with higher levels of methylation at these three IFI44L gene sites; c) the forced overexpression of IFI44L mRNA in two human lung cancer cell lines that express low levels of IFI44L mRNA, i.e., SPC-A1 cells (cells with characteristics of cancer stem cells{{cite journal | vauthors = Zhou CH, Yang SF, Li PQ | title = Human lung cancer cell line SPC-A1 contains cells with characteristics of cancer stem cells | journal = Neoplasma | volume = 59 | issue = 6 | pages = 685–92 | date = 2012 | pmid = 22862169 | doi = 10.4149/neo_2012_087 | url = }}) and LTEP-a-2 cells (i.e., cells used in Asian studies of lung cancer{{cite journal | vauthors = Mao Y, Yu Y, Han Y | title = Influence of thoracic drainage fluid on proliferation, migration, apoptosis, and drug resistance in lung cancer cell lines | journal = Cancer Management and Research | volume = 11 | issue = | pages = 2253–2259 | date = 2019 | pmid = 30962714 | pmc = 6433100 | doi = 10.2147/CMAR.S187019 | doi-access = free | url = }}) decreased their rate of proliferation and increased their apoptosis (i.e., cell death) while knockdown of the IFI44L gene in A549 cells, which normally express high levels of IFI44L, increased their rate of proliferation and decreased their apoptosis; and d) in a model of in vivo cancer cell growth, nude mice (i.e., mice with a defective immune system) that were subcutaneously injected with human lung cancer cells which overexpressed the IFI44Lgene grew more slowly than the tumors produced by the injection of human cancer cells that did not overexpress the IFI44l gene. These studies indicated that the IFI44L gene functions to inhibit the growth of certain types of human lung cancer cells in culture as well as in mice and suggest that this gene is a tumor suppressor gene.

A review of early stage lung cancers (127 patients), breast cancers (94 patients), and melanomas (15 patients) reported that the peripheral blood monocytes of these patients overexpressed the IFI44L protein compared to similar tissues taken form 148, 31, and 13, respectively, healthy individuals. While these results require further and independent validation, they suggest that high levels of the IFI44L protein may prove to be a useful biomarker for identifying these types of solid cancers at an early and perhaps more treatable stage.{{cite journal | vauthors = Chen S, Liu M, Liang B, Ge S, Peng J, Huang H, Xu Y, Tang X, Deng L | title = Identification of human peripheral blood monocyte gene markers for early screening of solid tumors | journal = PLOS ONE | volume = 15 | issue = 3 | pages = e0230905 | date = 2020 | pmid = 32226026 | pmc = 7105127 | doi = 10.1371/journal.pone.0230905 | doi-access = free | bibcode = 2020PLoSO..1530905C | url = }}

The Aicardi–Goutières syndrome (i.e., AGS) is a rare childhood genetic disorder caused by certain mutations in the TREX1, RNASEH2B, RNASEH2C, RNASEH2A, ADAR1, SAMHD1, IFIH1, LSM11, or RNU7-1 gene. Symptoms of the disease are most often detected in infants around 4 months of age but may be detectable in embryos.{{cite journal | vauthors = Liu A, Ying S | title = Aicardi-Goutières syndrome: A monogenic type I interferonopathy | journal = Scandinavian Journal of Immunology | volume = 98 | issue = 4 | pages = e13314 | date = October 2023 | pmid = 37515439 | doi = 10.1111/sji.13314 | url = }}{{cite journal | vauthors = Garau J, Charras A, Varesio C, Orcesi S, Dragoni F, Galli J, Fazzi E, Gagliardi S, Pansarasa O, Cereda C, Hedrich CM | title = Altered DNA methylation and gene expression predict disease severity in patients with Aicardi-Goutières syndrome | journal = Clinical Immunology (Orlando, Fla.) | volume = 249 | issue = | pages = 109299 | date = April 2023 | pmid = 36963449 | doi = 10.1016/j.clim.2023.109299 | url = | hdl = 11379/601985 | hdl-access = free }} These mutations lead to increased type I interferon production thereby triggering autoimmune inflammation-induced damage to nervous tissues that result in cerebral atrophy, various encephalopathies, spastic paraplegia, strokes, microcephaly, intellectual disability, epilepsy, bradykinesia (i.e., slowness in initiating voluntary movements), and/or dystonia (i.e., involuntary, repetitive muscle contractions).{{cite journal | vauthors = Dell'Isola GB, Dini G, Culpepper KL, Portwood KE, Ferrara P, Di Cara G, Verrotti A, Lodolo M | title = Clinical spectrum and currently available treatment of type I interferonopathy Aicardi-Goutières syndrome | journal = World Journal of Pediatrics | volume = 19 | issue = 7 | pages = 635–643 | date = July 2023 | pmid = 36650407 | pmc = 10258176 | doi = 10.1007/s12519-022-00679-2 | url = }} The elevated levels of type I interferons may also trigger inflammation-induced skin disorders such as chilblain-like lesions, acrocyanosis, fingernail abnormalities, the Raynaud syndrome, and/or endocrine diseases such as diabetes insipidus, diabetes mellitus, hyperparathyroidism, growth hormone deficiency, and adrenal insufficiency. A recent study showed that the blood levels of IFI44L mRNA: a) in 334 AGS patients were higher than those for 35 other interferon signaling genes and b) higher in 165 samples of patients with AGS compared to 574 samples of patients without AGS. The study suggested that elevated IFI44L mRNA blood levels may be a useful marker for diagnosing AGS.{{cite journal | vauthors = Adang LA, D'Aiello R, Takanohashi A, Woidill S, Gavazzi F, Behrens EM, Sullivan KE, Goldbach-Mansky R, de Jesus AA, Vanderver A, Shults J | title = IFN-signaling gene expression as a diagnostic biomarker for monogenic interferonopathies | journal = JCI Insight | volume = 9 | issue = 14 | pages = | date = June 2024 | pmid = 38885315 | pmc = 11383167 | doi = 10.1172/jci.insight.178456 | url = }} A study conducted in Italy examined patients with AGS caused by a mutation in the RNASEH2B gene. In addition to this mutation, 5 patients had a c.529G>A,p.A177T mutation in exon 7 of their two RNASEH2B genes. In this mutation, the guanine (G) nucleotide at gene position 529 is replaced by an adenine (A) nucleotide to result in changing the amino acid from alanine (A) to threonine (T) at position 177 in the mutated RNASEH2B protein.{{cite journal | vauthors = Videira G, Malaquias MJ, Laranjinha I, Martins R, Taipa R, Magalhães M | title = Diagnosis of Aicardi-Goutières Syndrome in Adults: A Case Series | journal = Movement Disorders Clinical Practice | volume = 7 | issue = 3 | pages = 303–307 | date = April 2020 | pmid = 32258229 | pmc = 7111574 | doi = 10.1002/mdc3.12903 | url = }} Five AGS patients who had this mutation in both of their RNASEH2B genes suffered far more severe forms of AGS than patients with this mutation in jnust one of their RNASEM2B genes. Patients with the adenine form of RNASEH2B mutated protein in both genes had low levels of methylation in the promotor regions of the IFI44L gene and significantly higher levels of IFI44L mRNA in their peripheral blood mononuclear cells. If these findings are confirmed in future studies, the authors suggest that high levels of IFI44L mRNA would be useful marker to diagnose AGS and support studies to determine if suppressing the expression of the IFI44L gene would be useful for treating AGS.

As reviewed by Zhao et al,{{cite journal | vauthors = Zhao X, Zhang L, Wang J, Zhang M, Song Z, Ni B, You Y | title = Identification of key biomarkers and immune infiltration in systemic lupus erythematosus by integrated bioinformatics analysis | journal = Journal of Translational Medicine | volume = 19 | issue = 1 | pages = 35 | date = January 2021 | pmid = 33468161 | pmc = 7814551 | doi = 10.1186/s12967-020-02698-x | doi-access = free | url = }} four studies found that IFI44L mRNA was more highly expressed in the peripheral blood monocytes, T helper cells, and B cells of patients with systemic lupus erythematosus (i.e., SLE) than healthy controls as measured using Affymetrix gene microarray chips. The review concluded that measuring the expression of IFI44L may be a useful step in diagnosing SLE. This conclusion was supported by two studies reporting that SLE patients had significantly higher levels of IFI44L mRNA in their peripheral blood{{cite journal | vauthors = Rodríguez-Carrio J, López P, Alperi-López M, Caminal-Montero L, Ballina-García FJ, Suárez A | title = IRF4 and IRGs Delineate Clinically Relevant Gene Expression Signatures in Systemic Lupus Erythematosus or Rheumatoid Arthritis | journal = Frontiers in Immunology | volume = 9 | issue = | pages = 3085 | date = 2018 | pmid = 30666255 | pmc = 6330328 | doi = 10.3389/fimmu.2018.03085 | doi-access = free | url = }} or peripheral blood mononuclear cells{{cite journal | vauthors = Wang Y, Jia W, Ma Q, Li F, Ma Z, Yang M, Pu J, Huo Z, Dang J | title = Identification of IFI44L as a new candidate molecular marker for systemic lupus erythematosus | journal = Clinical and Experimental Rheumatology | volume = 41 | issue = 1 | pages = 48–59 | date = January 2023 | pmid = 35349411 | doi = 10.55563/clinexprheumatol/q3aa6s | url = }} than healthy individuals. Similarly, a study of the Gene Expression Omnibus data set reported that 133 patients with SLE had higher levels of IFI44L mRNA in various types of their circulating blood cells compared to 62 healthy individuals.{{cite journal | vauthors = Cui Y, Zhang H, Wang Z, Gong B, Al-Ward H, Deng Y, Fan O, Wang J, Zhu W, Sun YE | title = Exploring the shared molecular mechanisms between systemic lupus erythematosus and primary Sjögren's syndrome based on integrated bioinformatics and single-cell RNA-seq analysis | journal = Frontiers in Immunology | volume = 14 | issue = | pages = 1212330 | date = 2023 | pmid = 37614232 | pmc = 10442653 | doi = 10.3389/fimmu.2023.1212330 | doi-access = free | url = }} A study of 1,521 patients with SLE, 782 patients with rheumatoid arthritis (i.e., RA), 199 patients with Sjögren's syndrome (i.e., SS), and 1,703 healthy individuals reported that the peripheral blood mononuclear cells of SLE patients had significantly lower DNA methylation levels in two promoter areas identified as Site1 (Chr1: 79 085 222) and Site2 (Chr1: 79 085 250; cg06872964) of their IFI44L genes than: a) RA patients, b) primary SS (i.e., pSS) patients (i.e., patients with SS that is not accompanied by any other systemic autoimmune disease), and c) healthy individuals.{{cite journal | vauthors = Zhao M, Zhou Y, Zhu B, Wan M, Jiang T, Tan Q, Liu Y, Jiang J, Luo S, Tan Y, Wu H, Renauer P, Del Mar Ayala Gutiérrez M, Castillo Palma MJ, Ortega Castro R, Fernández-Roldán C, Raya E, Faria R, Carvalho C, Alarcón-Riquelme ME, Xiang Z, Chen J, Li F, Ling G, Zhao H, Liao X, Lin Y, Sawalha AH, Lu Q | title = IFI44L promoter methylation as a blood biomarker for systemic lupus erythematosus | journal = Annals of the Rheumatic Diseases | volume = 75 | issue = 11 | pages = 1998–2006 | date = November 2016 | pmid = 26787370 | pmc = 4955646 | doi = 10.1136/annrheumdis-2015-208410 | url = }} Low methylation levels at gene promotors usually increase the expression of their gene's mRNA and protein.{{cite journal | vauthors = Maehara H, Kokaji T, Hatano A, Suzuki Y, Matsumoto M, Nakayama KI, Egami R, Tsuchiya T, Ozaki H, Morita K, Shirai M, Li D, Terakawa A, Uematsu S, Hironaka KI, Ohno S, Kubota H, Araki H, Miura F, Ito T, Kuroda S | title = DNA hypomethylation characterizes genes encoding tissue-dominant functional proteins in liver and skeletal muscle | journal = Scientific Reports | volume = 13 | issue = 1 | pages = 19118 | date = November 2023 | pmid = 37926704 | pmc = 10625943 | doi = 10.1038/s41598-023-46393-5 | bibcode = 2023NatSR..1319118M | url = }} A follow-up study found that the methylation levels in the IFI44L gene promotor were also lower in SLE patients than patients with discoid lupus erythematosus (i.e., a cutaneous and less severe form of SLE{{cite journal | vauthors = Vale EC, Garcia LC | title = Cutaneous lupus erythematosus: a review of etiopathogenic, clinical, diagnostic and therapeutic aspects | journal = Anais Brasileiros de Dermatologia | volume = 98 | issue = 3 | pages = 355–372 | date = 2023 | pmid = 36868923 | pmc = 10173173 | doi = 10.1016/j.abd.2022.09.005 | url = }}).{{cite journal | vauthors = Zhang B, Zhou T, Wu H, Zhao M, Lu Q | title = Difference of IFI44L methylation and serum IFN-a1 level among patients with discoid and systemic lupus erythematosus and healthy individuals | journal = Journal of Translational Autoimmunity | volume = 4 | issue = | pages = 100092 | date = 2021 | pmid = 33748734 | pmc = 7972957 | doi = 10.1016/j.jtauto.2021.100092 | url = }} The two studies suggested that low levels of methylations in the cited IFI44L gene promotor areas may be useful for diagnosing SLE and distinguishing SLE from RA, pSS, and discoid lupus erythematosus. A review of studies published up to July 2022 found 7 other reports showing that IFI44L gene promotor methylations were lower in SLE patients than healthy individuals. However, 2 of these 7 reports (both done in Iran) found that IFI44L promotor methylations were also lower in patients with rheumatoid arthritis than heathy individuals.{{cite journal | vauthors = Ehtesham N, Habibi Kavashkohie MR, Mazhari SA, Azhdari S, Ranjbar H, Mosallaei M, Hazrati E, Behroozi J | title = DNA methylation alterations in systemic lupus erythematosus: A systematic review of case-control studies | journal = Lupus | volume = 32 | issue = 3 | pages = 363–379 | date = March 2023 | pmid = 36573333 | doi = 10.1177/09612033221148099 | url = }} (As indicated in the next two sections, individuals with SS or RA overexpress the IFI44L gene.) This and another{{cite journal | vauthors = Mei X, Zhang B, Zhao M, Lu Q | title = An update on epigenetic regulation in autoimmune diseases | journal = Journal of Translational Autoimmunity | volume = 5 | issue = | pages = 100176 | date = 2022 | pmid = 36544624 | pmc = 9762196 | doi = 10.1016/j.jtauto.2022.100176 | url = }} review concluded that low methylation levels in an IFI44L gene promoter are a promising diagnostic biomarkers for SLE but further studies are needed to determine if a) these low levels do in fact discriminate SLE from RA, pSS, or other autoimmune diseases that can be mistaken for SLE and b) are related to the severity of SLE (e.g., is IFI44L promoter methylation low in mild cases of SLE?). Finally, a recent study found that 36 of 49 children with childhood-onset SLE had lower methylation levels in a promoter region of their IFI44L gene (measured in the children's whole blood) than those of 12 healthy children. The study suggested that, while further studies are needed, IFI44l promoter methylation levels in children appear similar to those found in adults.{{cite journal | vauthors = Wang J, Dang X, Wu X, Xiang Z, Li Y, Fu Y, Shen T | title = DNA methylation of IFI44L as a potential blood biomarker for childhood-onset systemic lupus erythematosus | journal = Pediatric Research | volume = 96 | issue = 2 | pages = 494–501 | date = July 2024 | pmid = 38514858 | pmc = 11343705 | doi = 10.1038/s41390-024-03135-1 | url = }}

Sjögren's syndrome (i.e., SS; also termed Sjögren's disease) is an autoimmune disease that typically involves inflammation-induce injuries to exocrine glands, particularly the lacrimal and salivary glands but also other organs such as the liver, kidney, and lung.{{cite journal | vauthors = Zhu W, Wang Y, Guan Y, Lu Y, Li Y, Sun L, Wang Y | title = Rapamycin can alleviate the submandibular gland pathology of Sjögren's syndrome by limiting the activation of cGAS-STING signaling pathway | journal = Inflammopharmacology | volume = 32 | issue = 2 | pages = 1113–1131 | date = April 2024 | pmid = 38114798 | doi = 10.1007/s10787-023-01393-9 | url = }} Patients with primary SS (i.e., pSS) have an increased incidence of developing various cancers such as non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, various leukemias, and cancers of the thyroid gland, skin (but not melanoma skin cancer), kidney, urinary tract, liver, and prostate gland.{{cite journal | vauthors = Zhong H, Liu S, Wang Y, Xu D, Li M, Zhao Y, Zeng X | title = Primary Sjögren's syndrome is associated with increased risk of malignancies besides lymphoma: A systematic review and meta-analysis | journal = Autoimmunity Reviews | volume = 21 | issue = 5 | pages = 103084 | date = May 2022 | pmid = 35341972 | doi = 10.1016/j.autrev.2022.103084 | url = }} An analysis of the parotid tissue of 18 patients with pSS found that it contained higher levels of IFI44L mRNA than the parotid's of 17 healthy individuals. This overexpression of the IFI44L gene was confirmed in studies that examined the parotid glands of 18 SS and 17 healthy individuals, the minor salivary glands of 9 SS and 8 healthy individuals, the blood mononuclear cells of 16 SS and 11 healthy individuals, the blood of 30 SS and 30 healthy individuals, and analyses of several Genome-wide association studies which found that 36 pSS patients had higher levels of IFI44L in various cell types of their peripheral blood compared to 24 healthy individuals. These studies suggested that overexpression of the IFI44L gene may be a useful marker for diagnosing and a potential target for treating SS. Finally, four other studies supported these conclusions by finding that the IFI44L gene was highly overexpressed in SS.

A study of 98 patients with Rheumatoid arthritis (i.e., RA) and 75 patients with SLE found that their peripheral blood contained significantly higher levels of IFI44L mRNA than 28 healthy individuals and that the IFI44L mRNA levels were significantly higher in SLE than RA patients. A study of DNA methylation in the IFI44L gene promoter in the peripheral blood mononuclear cells of 63 individuals with RA were significantly lower than that of 71 healthy individuals.{{cite journal | vauthors = Salesi M, Dehabadi MH, Salehi R, Salehi A, Pakzad B | title = Differentially methylation of IFI44L gene promoter in Iranian patients with systemic lupus erythematosus and rheumatoid arthritis | journal = Molecular Biology Reports | volume = 49 | issue = 4 | pages = 3065–3072 | date = April 2022 | pmid = 35059970 | doi = 10.1007/s11033-022-07134-5 | url = }} Other studies reported that patients with higher combination scores for the mRNA of IFI44L, MxA, OAS1, IFI6 and ISG15 genes in their peripheral whole blood and peripheral blood mononuclear cells developed within 6 months a more severe form of RA than patients with lower combination scores for these 5 interferon-stimulated genes. The study suggested that measurements of these 5 genes' expression may prove useful for determining the severity of RA.{{cite journal | vauthors = Cooles FA, Tarn J, Lendrem DW, Naamane N, Lin CM, Millar B, Maney NJ, Anderson AE, Thalayasingam N, Diboll J, Bondet V, Duffy D, Barnes MR, Smith GR, Ng S, Watson D, Henkin R, Cope AP, Reynard LN, Pratt AG, Isaacs JD | title = Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming | journal = Annals of the Rheumatic Diseases | volume = 81 | issue = 9 | pages = 1214–1223 | date = August 2022 | pmid = 35680389 | pmc = 9380486 | doi = 10.1136/annrheumdis-2022-222370 | url = }} Another study reported that the peripheral blood mononuclear cells of 35 RA patients had higher mRNA levels for the IFI44L, MX1, DTX3L, and PARP9 genes than 35 healthy individuals and suggested that these 4 interferon-stimulated genes are hub genes (i.e., genes that interact with other genes and thereby play essential roles in regulating other genes and various biological functions{{cite journal | vauthors = Yu D, Lim J, Wang X, Liang F, Xiao G | title = Enhanced construction of gene regulatory networks using hub gene information | journal = BMC Bioinformatics | volume = 18 | issue = 1 | pages = 186 | date = March 2017 | pmid = 28335719 | pmc = 5364645 | doi = 10.1186/s12859-017-1576-1 | doi-access = free | url = }}).{{cite journal | vauthors = Zhu H, Wu LF, Mo XB, Lu X, Tang H, Zhu XW, Xia W, Guo YF, Wang MJ, Zeng KQ, Wu J, Qiu YH, Lin X, Zhang YH, Liu YZ, Yi NJ, Deng FY, Lei SF | title = Rheumatoid arthritis-associated DNA methylation sites in peripheral blood mononuclear cells | journal = Annals of the Rheumatic Diseases | volume = 78 | issue = 1 | pages = 36–42 | date = January 2019 | pmid = 30297333 | doi = 10.1136/annrheumdis-2018-213970 | url = }}

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