Allograft inflammatory factor 1

The AIF1 gene is located within a segment of the major histocompatibility complex class III region. It has been shown that this gene is highly expressed in testis, spleen, and brain but weakly expressed in lung, and kidney. Among brain cells, the Iba1 gene is strongly and specifically expressed in microglia. Circulating macrophages also express Iba1.{{Citation needed|date=November 2021}}

AIF1 is a protein that exists in the cytoplasm, and it is highly evolutionarily conserved. It is also possibly identical to three other proteins, Iba-2, MRF-1 (microglia response factor) and daintain. However complete functional profiles of all three proteins and how they overlap is unknown.{{cite journal | vauthors = Deininger MH, Meyermann R, Schluesener HJ | title = The allograft inflammatory factor-1 family of proteins | journal = FEBS Letters | volume = 514 | issue = 2–3 | pages = 115–21 | date = March 2002 | pmid = 11943136 | doi = 10.1016/S0014-5793(02)02430-4 | s2cid = 34086133 | doi-access = free }} IBA1 is a 17-kDa EF hand protein that is specifically expressed in macrophages / microglia and is upregulated during the activation of these cells. Iba1 expression is up-regulated in microglia following nerve injury,{{cite journal | vauthors = Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S | title = Microglia-specific localisation of a novel calcium binding protein, Iba1 | journal = Brain Research. Molecular Brain Research | volume = 57 | issue = 1 | pages = 1–9 | date = June 1998 | pmid = 9630473 | doi = 10.1016/s0169-328x(98)00040-0 }} central nervous system ischemia, and several other brain diseases.

AIF1 was originally discovered in atherosclerotic lesions in a rat model of chronic allograft cardiac rejection. It was found to be upregulated in macrophages and neutrophils in response to the cytokine IFN-γ.{{cite journal | vauthors = Utans U, Arceci RJ, Yamashita Y, Russell ME | title = Cloning and characterization of allograft inflammatory factor-1: a novel macrophage factor identified in rat cardiac allografts with chronic rejection | journal = The Journal of Clinical Investigation | volume = 95 | issue = 6 | pages = 2954–62 | date = June 1995 | pmid = 7769138 | pmc = 295984 | doi = 10.1172/JCI118003 }} AIF1 expression has been seen to increase in vascular tissue in response to arterial injury, specifically it is found in activated vascular smooth muscle cells in response to IFN-γ, IL-1β, and T-cell conditioned media.{{cite journal | vauthors = Autieri MV, Carbone C, Mu A | title = Expression of allograft inflammatory factor-1 is a marker of activated human vascular smooth muscle cells and arterial injury | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 20 | issue = 7 | pages = 1737–44 | date = July 2000 | pmid = 10894811 | doi = 10.1161/01.ATV.20.7.1737 | doi-access = free }} In vascular smooth muscle cells, activation is responsible for arterial thickening in allografts through over proliferation. AIF1 has been found to enhance growth and promote proliferation in vascular smooth muscle cells through deregulation of the cell cycle. It does this by shortening the cell cycle and altering the expression of cyclins.{{cite journal | vauthors = Autieri MV, Carbone CM | title = Overexpression of allograft inflammatory factor-1 promotes proliferation of vascular smooth muscle cells by cell cycle deregulation | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 21 | issue = 9 | pages = 1421–6 | date = September 2001 | pmid = 11557666 | doi = 10.1161/hq0901.095566 | doi-access = free }} Though histologically different, AIF1 has also been shown to promote the proliferation and activation of endothelial cells (EC). EC activation, leads to proliferation and migration of cells, which is involved in multiple normal vascular processes, such as atherosclerosis, angiogenesis, and wound healing. It is currently theorized that AIF1 works to control endothelial cell proliferation and migration through action in signal transduction pathways.{{cite journal | vauthors = Tian Y, Jain S, Kelemen SE, Autieri MV | title = AIF-1 expression regulates endothelial cell activation, signal transduction, and vasculogenesis | journal = American Journal of Physiology. Cell Physiology | volume = 296 | issue = 2 | pages = C256-66 | date = February 2009 | pmid = 18787073 | pmc = 2643850 | doi = 10.1152/ajpcell.00325.2008 }} It has features of a cytoplasmic signaling protein, including several domains that allow for binding to multiprotein complexes, called PDZ domains.{{cite journal | vauthors = Hung AY, Sheng M | title = PDZ domains: structural modules for protein complex assembly | journal = The Journal of Biological Chemistry | volume = 277 | issue = 8 | pages = 5699–702 | date = February 2002 | pmid = 11741967 | doi = 10.1074/jbc.R100065200 | doi-access = free}} In endothelial cells, AIF1 has been specifically shown to regulate vasculogenesis, including the formation of aortic sprouting and tube-like formations. AIF1 been shown to interact with kinase p44/42 and PAK1, two previously known signal transduction molecules, in regulating these processes. AIF1 also shows distinct differences in the pathways by which it regulates endothelial cells, macrophages, and vascular smooth muscle cells. Upregulation of AIF-1 is connected with increased migration of mononuclear peripheral blood cell. In the CD14 positive cells, AIF-1 support secretion of IL-6 and various chemokines.{{cite journal | vauthors = Kadoya M, Yamamoto A, Hamaguchi M, Obayashi H, Mizushima K, Ohta M, Seno T, Oda R, Fujiwara H, Kohno M, Kawahito Y | display-authors = 6 | title = Allograft inflammatory factor-1 stimulates chemokine production and induces chemotaxis in human peripheral blood mononuclear cells | journal = Biochemical and Biophysical Research Communications | volume = 448 | issue = 3 | pages = 287–91 | date = June 2014 | pmid = 24796669 | doi = 10.1016/j.bbrc.2014.04.106 }} AIF-1 may also play a role in the T-cell response. It has been shown that AIF-1 increases expression of IL-2 and IFN-γ in T-cells, while the expression of IL-4 and TGF-β is decreased. The presence of AIF-1 also inhibits polarization into regulatory T cells.{{cite journal | vauthors = Cano-Martínez D, Monserrat J, Hernández-Breijo B, Sanmartín Salinas P, Álvarez-Mon M, Val Toledo-Lobo M, Guijarro LG | title = Extracellular allograft inflammatory factor-1 (AIF-1) potentiates Th1 cell differentiation and inhibits Treg response in human peripheral blood mononuclear cells from normal subjects | journal = Human Immunology | volume = 81 | issue = 2–3 | pages = 91–100 | date = February 2020 | pmid = 32057519 | doi = 10.1016/j.humimm.2020.01.011 | s2cid = 211112950 }}

Allograft Inflammatory Factor 1 is found in activated macrophages. Activated macrophages are found in tissues with inflammation. AIF1 levels in healthy humans have been found to positively correlate with metabolic indicators, such as body mass index, triglycerides, and fasting plasma glucose levels. The excess of adipose tissue found in obese patients is found to cause chronic inflammation with an increase in the number of activated macrophages. Subsequently, AIF1 may be an accurate indicator of macrophage activation in the body.{{cite journal | vauthors = Fukui M, Tanaka M, Toda H, Asano M, Yamazaki M, Hasegawa G, Imai S, Fujinami A, Ohta M, Nakamura N | display-authors = 6 | title = The serum concentration of allograft inflammatory factor-1 is correlated with metabolic parameters in healthy subjects | journal = Metabolism | volume = 61 | issue = 7 | pages = 1021–5 | date = July 2012 | pmid = 22225958 | doi = 10.1016/j.metabol.2011.12.001 }} There is also evidence that AIF1 could be a marker for diabetic nephropathy when detected in serum.{{cite journal | vauthors = Fukui M, Tanaka M, Asano M, Yamazaki M, Hasegawa G, Imai S, Fujinami A, Ohta M, Obayashi H, Nakamura N | display-authors = 6 | title = Serum allograft inflammatory factor-1 is a novel marker for diabetic nephropathy | journal = Diabetes Research and Clinical Practice | volume = 97 | issue = 1 | pages = 146–50 | date = July 2012 | pmid = 22560794 | doi = 10.1016/j.diabres.2012.04.009 }} Since diabetic nephropathy is a consequence of long-term type 1 and type 2 diabetes, this consistent with evidence that AIF1 may be associated with other aspects of diabetes. It is found in activated macrophages in the pancreatic islets, and has been shown to decrease insulin secretion, while simultaneously impairing glucose elimination.{{cite journal | vauthors = Chen ZW, Ahren B, Ostenson CG, Cintra A, Bergman T, Möller C, Fuxe K, Mutt V, Jörnvall H, Efendic S | display-authors = 6 | title = Identification, isolation, and characterization of daintain (allograft inflammatory factor 1), a macrophage polypeptide with effects on insulin secretion and abundantly present in the pancreas of prediabetic BB rats | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 25 | pages = 13879–84 | date = December 1997 | pmid = 9391121 | pmc = 28401 | doi = 10.1073/pnas.94.25.13879 | bibcode = 1997PNAS...9413879C | doi-access = free }}

In recent years, the possibility of a role for AIF-1 in cancer development has also been considered. Significantly higher levels of AIF-1 expression were found in hepatocarcinoma cell lines and in tissue compared to healthy samples. One option in which AIF-1 may contribute to the development of pathology is involvement in the proliferation and migration of tumor cells.{{cite journal | vauthors = Zhang Q, Sun S, Zhu C, Xie F, Cai Q, Sun H, Chen G, Liang X, Xie H, Shi J, Liao Y, Zhou J | display-authors = 6 | title = Expression of Allograft Inflammatory Factor-1 (AIF-1) in Hepatocellular Carcinoma | journal = Medical Science Monitor | volume = 24 | pages = 6218–6228 | date = September 2018 | pmid = 30188879 | pmc = 6139115 | doi = 10.12659/MSM.908510 }} It was also shown that AIF-1 promote cell proliferation in the breast cancer cells line. This effect was dependent on time and level of AIF-1 protein.{{cite journal | vauthors = Yu Z, Song YB, Cui Y, Fu AQ | title = Effects of AIF-1 inflammatory factors on the regulation of proliferation of breast cancer cells | journal = Journal of Biological Regulators and Homeostatic Agents | volume = 33 | issue = 4 | pages = 1085–1095 | date = July 2019 | pmid = 31389223 }} Upregulation of AIF-1 enhanced activity of NF-ΚB and increased expression of cyclin D1. Cyclin D1 contribute to cell proliferation and mutation in this gene has been connected with variety of tumors. It has also been shown that AIF-1 expression can contribute to progression of cancer by inhibition of apoptosis in cells.{{cite journal | vauthors = Jia S, Chaibou MA, Chen Z | title = Daintain/AIF-1 reinforces the resistance of breast cancer cells to cisplatin | journal = Bioscience, Biotechnology, and Biochemistry | volume = 76 | issue = 12 | pages = 2338–41 | date = 2012-12-23 | pmid = 23221708 | doi = 10.1271/bbb.120577 | s2cid = 883243 }}{{cite journal | vauthors = Liu S, Tan WY, Chen QR, Chen XP, Fu K, Zhao YY, Chen ZW | title = Daintain/AIF-1 promotes breast cancer proliferation via activation of the NF-kappaB/cyclin D1 pathway and facilitates tumor growth | journal = Cancer Science | volume = 99 | issue = 5 | pages = 952–7 | date = May 2008 | pmid = 18341653 | doi = 10.1111/j.1349-7006.2008.00787.x | s2cid = 5167641 | doi-access = | pmc = 11159275 }}

The role of up-regulation of expression of AIF-1 was demonstrated in rheumatoid arthritis. Presence of AIF-1 was confirmed in synovial tissue of patient with this pathology. AIF-1 was strongly expressed in several cell types of synovial tissue, such as fibroblast and synovial cells, but also in infiltrated immune cells. It was also shown that upregulation of AIF-1 contribute to induction of enhances the production of IL-6 . Another factor by which the expression of AIF-1 affects the course of the disease is increased proliferation of synovial cells.{{cite journal | vauthors = Kimura M, Kawahito Y, Obayashi H, Ohta M, Hara H, Adachi T, Tokunaga D, Hojo T, Hamaguchi M, Omoto A, Ishino H, Wada M, Kohno M, Tsubouchi Y, Yoshikawa T | display-authors = 6 | title = A critical role for allograft inflammatory factor-1 in the pathogenesis of rheumatoid arthritis | journal = Journal of Immunology | volume = 178 | issue = 5 | pages = 3316–22 | date = March 2007 | pmid = 17312183 | doi = 10.4049/jimmunol.178.5.3316 | doi-access = free }}

AIF-1 was also considered as a player in the diseases connected with fibrosis. For example, in kidney diseases overexpression of AIF-1 in the macrophages contributes to signaling through AKT and mTOR. Another way in which AIF-1 contribute to the pathology of kidney is upregulation of enzyme NADPH oxidase 2. This upregulation leads to oxidative stress in the cells and progression of renal injury.{{cite journal | vauthors = Yuan X, Wang X, Li Y, Li X, Zhang S, Hao L | title = Aldosterone promotes renal interstitial fibrosis via the AIF‑1/AKT/mTOR signaling pathway | journal = Molecular Medicine Reports | volume = 20 | issue = 5 | pages = 4033–4044 | date = November 2019 | pmid = 31545432 | pmc = 6797939 | doi = 10.3892/mmr.2019.10680 }} Expression of AIF-1 is considered to be linked with calcification in hemodyalisis patients. Higher presence of AIF-1/NF-κB/MCP-1/CCR-2-pathway was detected in calcifaied vascular smooth muscle cells. AIF-1 was also detected as a potential factor which contribue to apoptosis and inflammation.{{cite journal | vauthors = Hao J, Tang J, Zhang L, Li X, Hao L | title = The Crosstalk between Calcium Ions and Aldosterone Contributes to Inflammation, Apoptosis, and Calcification of VSMC via the AIF-1/NF-κB Pathway in Uremia | journal = Oxidative Medicine and Cellular Longevity | volume = 2020 | pages = 3431597 | date = 2020-12-04 | pmid = 33343805 | pmc = 7732390 | doi = 10.1155/2020/3431597 | veditors = Muntean D | doi-access = free }}

Since the immune response in the retina is tightly regulated under physiological conditions, microglia may play a role in retinal diseases.{{cite journal | vauthors = Okunuki Y, Mukai R, Nakao T, Tabor SJ, Butovsky O, Dana R, Ksander BR, Connor KM | display-authors = 6 | title = Retinal microglia initiate neuroinflammation in ocular autoimmunity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 20 | pages = 9989–9998 | date = May 2019 | pmid = 31023885 | pmc = 6525481 | doi = 10.1073/pnas.1820387116 | bibcode = 2019PNAS..116.9989O | doi-access = free }} Retinitis pigmentosa is an inherited disease in which photoreceptors are gradually degenerated. That condition gradually leads to reduced of dark vision and eventually complete blindness. In an experimental model RCS (The Royal College of Surgeons) rats with progression loss of photoreceptors, level of AIF-1 was elevated in retina in contrast to wild type{{cite journal | vauthors = Lew DS, Mazzoni F, Finnemann SC | title = Microglia Inhibition Delays Retinal Degeneration Due to MerTK Phagocytosis Receptor Deficiency | journal = Frontiers in Immunology | volume = 11 | issue = | pages = 1463 | date = 2020 | pmid = 32765507 | pmc = 7381113 | doi = 10.3389/fimmu.2020.01463 | doi-access = free }}

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• {{cite journal | vauthors = Deininger MH, Meyermann R, Schluesener HJ | title = The allograft inflammatory factor-1 family of proteins | journal = FEBS Letters | volume = 514 | issue = 2–3 | pages = 115–21 | date = March 2002 | pmid = 11943136 | doi = 10.1016/S0014-5793(02)02430-4 | s2cid = 34086133 | doi-access = free }}
• {{cite journal | vauthors = Utans U, Arceci RJ, Yamashita Y, Russell ME | title = Cloning and characterization of allograft inflammatory factor-1: a novel macrophage factor identified in rat cardiac allografts with chronic rejection | journal = The Journal of Clinical Investigation | volume = 95 | issue = 6 | pages = 2954–62 | date = June 1995 | pmid = 7769138 | pmc = 295984 | doi = 10.1172/JCI118003 }}
• {{cite journal | vauthors = Iris FJ, Bougueleret L, Prieur S, Caterina D, Primas G, Perrot V, Jurka J, Rodriguez-Tome P, Claverie JM, Dausset J | display-authors = 6 | title = Dense Alu clustering and a potential new member of the NF kappa B family within a 90 kilobase HLA class III segment | journal = Nature Genetics | volume = 3 | issue = 2 | pages = 137–45 | date = February 1993 | pmid = 8499947 | doi = 10.1038/ng0293-137 | s2cid = 33041319 }}
• {{cite journal | vauthors = Utans U, Quist WC, McManus BM, Wilson JE, Arceci RJ, Wallace AF, Russell ME | title = Allograft inflammatory factory-1. A cytokine-responsive macrophage molecule expressed in transplanted human hearts | journal = Transplantation | volume = 61 | issue = 9 | pages = 1387–92 | date = May 1996 | pmid = 8629302 | doi = 10.1097/00007890-199605150-00018 | doi-access = free }}
• {{cite journal | vauthors = Autieri MV, Agrawal N | title = IRT-1, a novel interferon-gamma-responsive transcript encoding a growth-suppressing basic leucine zipper protein | journal = The Journal of Biological Chemistry | volume = 273 | issue = 24 | pages = 14731–7 | date = June 1998 | pmid = 9614071 | doi = 10.1074/jbc.273.24.14731 | doi-access = free }}
• {{cite journal | vauthors = Neville MJ, Campbell RD | title = A new member of the Ig superfamily and a V-ATPase G subunit are among the predicted products of novel genes close to the TNF locus in the human MHC | journal = Journal of Immunology | volume = 162 | issue = 8 | pages = 4745–54 | date = April 1999 | doi = 10.4049/jimmunol.162.8.4745 | pmid = 10202016 | doi-access = free }}
• {{cite journal | vauthors = Sasaki Y, Ohsawa K, Kanazawa H, Kohsaka S, Imai Y | title = Iba1 is an actin-cross-linking protein in macrophages/microglia | journal = Biochemical and Biophysical Research Communications | volume = 286 | issue = 2 | pages = 292–7 | date = August 2001 | pmid = 11500035 | doi = 10.1006/bbrc.2001.5388 }}
• {{cite journal | vauthors = Autieri MV, Kelemen SE, Wendt KW | title = AIF-1 is an actin-polymerizing and Rac1-activating protein that promotes vascular smooth muscle cell migration | journal = Circulation Research | volume = 92 | issue = 10 | pages = 1107–14 | date = May 2003 | pmid = 12714565 | doi = 10.1161/01.RES.0000074000.03562.CC | doi-access = free }}
• {{cite journal | vauthors = Deininger MH, Weinschenk T, Meyermann R, Schluesener HJ | title = The allograft inflammatory factor-1 in Creutzfeldt-Jakob disease brains | journal = Neuropathology and Applied Neurobiology | volume = 29 | issue = 4 | pages = 389–99 | date = August 2003 | pmid = 12887599 | doi = 10.1046/j.1365-2990.2003.00476.x | s2cid = 21401126 | doi-access = free }}
• {{cite journal | vauthors = Xie T, Rowen L, Aguado B, Ahearn ME, Madan A, Qin S, Campbell RD, Hood L | display-authors = 6 | title = Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse | journal = Genome Research | volume = 13 | issue = 12 | pages = 2621–36 | date = December 2003 | pmid = 14656967 | pmc = 403804 | doi = 10.1101/gr.1736803 }}
• {{cite journal | vauthors = Ohsawa K, Imai Y, Sasaki Y, Kohsaka S | title = Microglia/macrophage-specific protein Iba1 binds to fimbrin and enhances its actin-bundling activity | journal = Journal of Neurochemistry | volume = 88 | issue = 4 | pages = 844–56 | date = February 2004 | pmid = 14756805 | doi = 10.1046/j.1471-4159.2003.02213.x | s2cid = 25092822 | doi-access = }}
• {{cite journal | vauthors = Chen X, Kelemen SE, Autieri MV | title = AIF-1 expression modulates proliferation of human vascular smooth muscle cells by autocrine expression of G-CSF | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 24 | issue = 7 | pages = 1217–22 | date = July 2004 | pmid = 15117732 | doi = 10.1161/01.ATV.0000130024.50058.de | doi-access = free }}
• {{cite journal | vauthors = Arvanitis DA, Flouris GA, Spandidos DA | title = Genomic rearrangements on VCAM1, SELE, APEG1and AIF1 loci in atherosclerosis | journal = Journal of Cellular and Molecular Medicine | volume = 9 | issue = 1 | pages = 153–9 | year = 2005 | pmid = 15784173 | pmc = 6741330 | doi = 10.1111/j.1582-4934.2005.tb00345.x }}
• {{cite journal | vauthors = Autieri MV, Chen X | title = The ability of AIF-1 to activate human vascular smooth muscle cells is lost by mutations in the EF-hand calcium-binding region | journal = Experimental Cell Research | volume = 307 | issue = 1 | pages = 204–11 | date = July 2005 | pmid = 15922740 | doi = 10.1016/j.yexcr.2005.03.002 }}

{{refend}}

• {{UCSC gene info|AIF1}}
• [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P55008 PDBe-KB] provides an overview of all the structure information available in the PDB for Human Allograft inflammatory factor 1

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Category:EF-hand-containing proteins