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At least 19 recordsLinked to original sources

PubMed2006

Crystallization and preliminary crystallographic analysis of allograft inflammatory factor 1.

Allograft inflammatory factor-1 (AIF-1) is a 17-kDa IFN-gamma inducible Ca2+-binding EF-hand protein involved in immune dysfunction and smooth muscle cell activation. AIF-1 was solubly expressed in E. coli and purified. Crystals of AIF-1 were grown at 291 K using PEG-8000 as precipitant. Diffraction by the AIF-1 crystal extends to 3.3 A resolution, and the crystal belongs to the space group P4(3) with unit cell parameters a=b=73.4, c=49.1 A.

Calcium-Binding Proteins↗

PubMed1999

Differential expression of allograft inflammatory factor 1 and of glutathione peroxidase during auto- and allograft response in marine sponges.

Very recently, Porifera (sponges) have been proven to be suitable model systems to study auto- and allograft recognition at the molecular level. Several potential immune molecules have been isolated from the marine sponges Suberites domuncula and Geodia cydonium, among them those which comprise Ig-like domains in their extracellular part. Here we report on the isolation of two cDNAs from S. domuncula that code for molecules involved in mammals in cytokine-mediated graft response; a putative allograft inflammatory factor 1 (AIF-1) and a non-selenium glutathione peroxidase (GPX). Both polypeptides share high similarity with the corresponding mammalian proteins. The expression of the two genes during auto- and allograft recognition in S. domuncula and G. cydonium was determined. It is shown that the expression of the AIF-1-related gene is upregulated only in allografts, while the GPX-related gene is expressed in the fusion zones formed between auto- as well as allografts. Taken together, these findings suggest that besides cell-mediated defense reactions a cytokine-dependent immune response is also elicited during graft recognition in sponges.

Amino Acid Sequence↗

PubMed2006

Expression of allograft inflammatory factor 1 in tissues from patients with systemic sclerosis and in vitro differential expression of its isoforms in response to transforming growth factor beta.

OBJECTIVE: Allograft inflammatory factor 1 (AIF-1), a protein initially identified in chronically rejected rat cardiac allografts, is involved in the immune response and proliferative vasculopathy that occurs during allograft rejection. Three well-characterized isoforms of AIF-1 result from alternative messenger RNA (mRNA) splicing. We previously identified a strong association of systemic sclerosis (SSc) with a polymorphism in AIF-1 isoform 2. The purpose of this study was to investigate AIF-1 expression in affected tissues from patients with SSc and to examine the regulation of its isoforms by transforming growth factor beta (TGFbeta). METHODS: AIF-1 in the skin and lung tissues of patients with SSc was analyzed by immunochemistry. AIF-1 isoform expression in response to TGFbeta and interferon-gamma stimulation was examined by quantitative polymerase chain reaction (PCR). RESULTS: AIF-1 protein was present in affected vessels of the lung and skin lesions of patients with SSc. Quantitative PCR showed an average of 14-fold higher mRNA levels in affected SSc skin than in normal skin. Double-label immunofluorescence staining demonstrated that T cells, macrophages, and endothelial cells in affected tissues expressed AIF-1. Stimulation of peripheral blood mononuclear cells with TGFbeta caused a specific and significant increase in the expression of AIF-1 isoform 2 transcripts (P < 0.005), which was due to stabilization of AIF-1 isoform 2 mRNA. CONCLUSION: These data suggest that AIF-1 plays an important role in the pathogenesis of SSc owing to its increased expression in affected tissues and to the specific stimulation of AIF-1 isoform 2 by TGFbeta.

Calcium-Binding Proteins↗

PubMed2000

"Allograft-inflammatory-factor-1 is upregulated in microglial cells in human cerebral infarctions".

Allograft inflammatory factor-1 (AIF-1) is a 17-kDa-peptide identified in rat cardiac allografts undergoing chronic rejection and in activated microglial cells in inflammatory autoimune disease of the CNS. We have investigated the expression of AIF-1 in 18 autopsy cases of human focal cerebral infarction. AIF-1-positive cells show the morphology of microglia and are CD68- but not GFAP-positive. The peptide is expressed at a low level in normal brain. In infarctions, activated microglial cells in the area of glial reaction show strongly enhanced cytoplasmic immunoreactivity. The density of AIF-1-expressing cells increases during the first three days post infarction and remains elevated until chronic cystic stages. The upregulation of AIF-1-immunoreactivity precedes the rise in expression of the S-100-protein MRP-8. We conclude that AIF-1 is a sensitive marker of human microglial activation not only in inflammation but also in non-inflammatory lesions of the CNS.

Aged↗

PubMed2000

Allograft-inflammatory-factor-1 is upregulated in microglial cells in human cerebral infarctions.

Aged↗

PubMed2006

The role of allograft inflammatory factor 1 in systemic sclerosis.

PURPOSE OF REVIEW: The aim of this article is to review studies which support the hypothesis that allograft inflammatory factor-1, a protein initially identified in chronically rejected cardiac allografts, may be involved in the pathogenesis of the progressive fibroproliferative vasculopathy which is a hallmark of systemic sclerosis. RECENT FINDINGS: Recent findings demonstrated elevated allograft inflammatory factor-1 expression both in systemic sclerosis affected tissues and peripheral blood mononuclear cells. A detailed immunohistopathologic study examined the tissue and cellular localization of the protein in affected systemic sclerosis tissues and demonstrated its expression in the endothelium of dermal and pulmonary vessels, in the pulmonary parenchyma, and in relevant inflammatory cells including T cells and macrophages. Furthermore, functional studies showed specific allograft inflammatory factor-1 isoform expression stimulation by transforming growth factor-beta. SUMMARY: This review summarizes recent findings suggesting that allograft inflammatory factor-1 may play an important role in systemic sclerosis vasculopathy and provides supporting evidence to consider the molecule as a novel therapeutic target.

Biomarkers↗

PubMed2002

Histocompatibility reaction in tissue and cells of the marine sponge Suberites domuncula in vitro and in vivo: central role of the allograft inflammatory factor 1.

Sponges (Porifera) are the phylogenetically oldest still extant metazoan phylum. Recently elements of their immune system have been cloned and analyzed, primarily from the demosponges Suberites domuncula and Geodia cydonium. By differential display, two genes were identified in S. domuncula, whose translation products are involved in graft rejection/fusion: the allograft inflammatory factor (AIF-1) and the Tcf-like transcription factor (TCF). Since the AIF-1 and TCF genes are upregulated in vivo after tissue transplantation, especially in allografts, we investigated whether this reaction can be monitored in vitro. Therefore, the autogeneic and the allogeneic mixed sponge cell reaction (MSCR) system was applied for the first time to identify distinct factors in sponges in vitro. The results confirm that the two AIF-1 and TCF genes are induced during allogeneic MSCR. Furthermore, the recombinant sponge AIF-1 causes an upregulation of the expression of the TCF. We conclude that the AIF-1 and TCF genes are upregulated in sponges during histoincompatibility reactions; the data support the view that sponges have immune systems composed of highly complex elements related to those found in mammalian systems.

Amino Acid Sequence↗

PubMed1997

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.

A bioactive macrophage factor, the polypeptide daintain/allograft inflammatory factor 1 (AIF1), has been isolated from porcine intestine. It was discovered when searching for intestinal peptides with effects on insulin release, and its purification was monitored by the influence of the peptide fractions on pancreatic glucose-induced insulin secretion. Daintain/AIF1 is a 146-aa residue polypeptide with a mass of 16,603 Da and an acetylated N terminus. An internal 44-residue segment with the sequence pattern -KR-KK-GKR- has a motif typical of peptide hormone precursors, i.e., dibasic sites for potential activation cleavages and at the sequentially last such site, the structure GKR. The latter is a signal for C-terminal amide formation in the processing of peptide hormones. Daintain/AIF1 is immunohistochemically localized to microglial cells in the central nervous system and to dendritic cells and macrophages in several organs. A particularly dense accumulation of daintain/AIF1-immunoreactive macrophages was observed in the insulitis affecting the pancreatic islets of prediabetic BB rats. When injected intravenously in mice, daintain/AIF1 at 75 pmol/kg inhibited glucose (1 g/kg)-stimulated insulin secretion, with a concomitant impairment of the glucose elimination, whereas at higher doses (7.5 and 75 nmol/kg), daintain/AIF1 potentiated glucose-stimulated insulin secretion and enhanced the glucose elimination. Its dual influence on insulin secretion in vivo at different peptide concentrations, and the abundance of macrophages expressing daintain/AIF1 in the pancreatic islets of prediabetic rats, suggest that daintain/AIF1 may have a role in connection with the pathogenesis of insulin-dependent diabetes mellitus.

Amino Acid Sequence↗

PubMed2003

TNF, TNF receptor type 1, and allograft inflammatory factor-1 gene polymorphisms in Japanese patients with type 1 diabetes.

The human leukocyte antigen (HLA) class III region, located on chromosome 6p21, has been regarded as one of the susceptible loci for type 1 diabetes. Because it contains many genes related to inflammatory and immune responses, including tumor necrosis factor (TNF), lymphotoxin-alpha (LT-alpha), and allograft inflammatory factor 1 (AIF-1) genes, it is unclear which gene within the class III region is responsible for the susceptibility to the disease. We sequenced the AIF-1 gene region and detected three novel polymorphisms, all of which were diallelic and localized at introns. Then, we investigated AIF-1, TNF, and LT-alpha gene polymorphisms in 165 patients with type 1 diabetes, consisting of 90 patients with young-onset type 1 diabetes, 75 patients with adult-onset type 1 diabetes, and 200 control patients. We also analyzed TNF receptors type 1 (TNFR1) and type 2 (TNFR2) gene polymorphisms, located on chromosome 12p13 and 1p36, respectively. Although there were significant differences between type 1 diabetes patients and controls in the distributions of TNF promoter polymorphisms at position -1031 and -857, and LT-alpha gene NcoI polymorphism, none of them was independently associated with the disease after two-locus analysis with HLA class II alleles. We detected the significantly increased frequency of the -383C allele, located in the TNFR-1 promoter region, in both young-onset and adult-onset diabetes patients compared with controls. In addition, the -383C allele was found to be associated with higher expression of the TNFR1 gene than that of -383A allele in in vitro expression. These results suggest that the TNFR1 gene region might be a susceptible locus to type 1 diabetes in Japanese.

Adult↗

PubMed2005

Haplotype analysis of a 100 kb region spanning TNF-LTA identifies a polymorphism in the LTA promoter region that is associated with atopic asthma susceptibility in Japan.

BACKGROUND: The tumour necrosis factor (TNF) gene family, which includes TNF, LTA, and LTB, is located consecutively on human chromosome 6p21 region, which has been linked to asthma by several genome-wide screens. (LTA, lymphotoxin-alpha; LTB, lymphotoxin-beta). OBJECTIVE: The aim of the present study was to determine whether genes on 6q21 are related to development of atopic asthma. Methods We screened for mutations in the coding and promoter regions of genes in the TNF-LTA region, including BAT1, NFKBIL1, LTA, TNF, LTB, AIF, and BAT2, and conducted a transmission disequilibrium test of 41 polymorphisms in 137 families identified through pro-bands with childhood-onset atopic asthma. (BAT1, HLA-B-associated transcript 1; NFKBIL1, nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor-like 1; AIF, allograft inflammatory factor 1). RESULTS: Haplotypes of the LTA/TNF linkage disequilibrium block were associated significantly with asthma (global P=0.0097). Transmission patterns of the common haplotypes to asthmatic offspring were predicted by a single-nucleotide polymorphism in the LTA promoter region. The G allele of the LTA-753G/A polymorphism was transmitted preferentially to asthma-affected individuals (P=0.001). Luciferase reporter assays with constructs containing the 5' and 3' flanking regions of the LTA gene showed 30-50% lower transcriptional activity when the -753A allele was present than that of other haplotypes. CONCLUSION: Our results suggest that LTA is one of the genes that contributes to susceptibility to atopic asthma, and that the association of the TNF/LTA haplotypes to asthma may be defined by the polymorphism in the LTA promoter region in the Japanese population.

Adolescent↗

PubMed1999

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.

It is becoming increasingly apparent that many of the genes in the class III region of the human MHC encode proteins involved in the immune and inflammatory responses. Furthermore, genetic studies have indicated that genes within the class III region, particularly the telomeric segment containing the TNF gene, could contribute to susceptibility to diseases of immune-related etiology. We have sequenced an 82-kb segment of DNA around the TNF gene to identify candidate disease susceptibility genes in this region. The 10 known genes in this region have been precisely positioned with the order allograft inflammatory factor 1, G1, 1C7, leukocyte-specific transcript 1 (B144), lymphotoxin B, TNF, lymphotoxin A, NB6, IKBL, BAT1 (centromere to telomere), and their genomic structures have been defined. Comparison of the G1 genomic region with previously described cDNA and genomic sequences, together with the results of reverse transcriptase-PCR, indicates that three alternative transcripts, G1, allograft inflammatory factor 1, and IFN-gamma-responsive transcript, are all derived from this gene. The completion of the sequence of 1C7 (D6S2570) has revealed that this gene encodes a putative novel member of the Ig superfamily. A number of alternatively spliced transcripts of 1C7 were identified by reverse transcriptase-PCR, all of which are expressed in immune-related cell lines. Alternative splicing within the Ig domain-encoding region was seen to result in possible set switching between an IgV domain and an IgC2 domain. Lastly, a previously unidentified gene, homologous to a number of V-ATPase G subunits, has been located 1 kb telomeric of IKBL.

Alternative Splicing↗

PubMed1997

Sustained anti-CD4/CD8 treatment blocks inflammatory activation and intimal thickening in mouse heart allografts.

We evaluated inflammatory activation and vascular thickening in a heterotopic murine heart transplant model. C57BL/6J recipient mice received anti-CD4 therapy (days 1 to 4 after transplantation) or sustained, combined anti-CD4/CD8 therapy (days 1 to 4, weekly thereafter). Morphometric analysis of grafts (> 95 days) found the mean percentage of vessel occlusion to be 51.7% in allografts treated with anti-CD4, 8.3% in allografts treated with sustained anti-CD4/CD8, and 6.7% in isografts. Mean transcript levels of the adhesion molecules P-selectin, intercellular adhesion molecule 1 (ICAM-1), and leukocyte function-associated antigen 1 (LFA-1) and the cytokines interleukin 4 (IL-4), interferon-gamma (IFN-gamma), inducible nitric oxide synthase (iNOS), allograft inflammatory factor 1 (AIF-1), and monocyte chemoattractant protein 1 (MCP-1) were measured with reverse transcription-polymerase chain reaction [RT-PCR] assays using deoxycytidine triphosphate radiolabeled with phosphorus 32 [32P-dCTP]. The assays were normalized against glyceraldehyde-3-phosphate dehydrogenase [G3PDH] Levels were found to be significantly higher in the anti-CD4 group than in the anti-CD4/CD8 group. A strong correlation was also found between the percentage of luminal occlusion and the expression of these markers of inflammation (r = .92-.99, P < .0001). Sustained therapy involving proximal blockade of CD4 and CD8 interrupts pathways leading to inflammation and vascular thickening. However, long-term heart allografts in mice treated with a short course of anti-CD4 display an ongoing inflammatory cell activation that culminates in arteriosclerosis. This model may help examine the role of targeted immune factors using knockout mice to identify those causally involved in vessel thickening.

Animals↗

PubMed2004

Gene expression profiling in chronic inflammatory demyelinating polyneuropathy.

Gene expression in archived frozen sural nerve biopsies of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) was compared to that in vasculitic nerve biopsies (VAS) and to normal nerve (NN) by DNA microarray technology. Hierarchical clustering analysis demonstrated distinct gene expression patterns distinguishing these disease groups. Of particular interest were: (1) Tachykinin precursor 1, which may be involved in pain mediation; (2) Stearoyl-CoA-desaturase, which may be a marker for remyelination and (3) the Allograft Inflammatory Factor 1 (AIF-1), a modulator of immune response during macrophage activation. Differential gene expression may help distinguish between CIDP, VAS and NN in sural nerve biopsies and identify genes that may be involved in disease pathogenesis.

Adult↗

PubMed2003

Influence of local complications on capsule formation around model implants in a rat model.

We studied the capsule formation around various filled breast implants and other related changes in distant organs (e.g., liver, spleen, lymph nodes) in a rat model 3 and 6 months after implantation. Model implants, one per rat, (filled with saline, n = 19; silicone, n = 14; cohesive silicone, n = 17; and hydrogel, n = 19) were implanted subcutaneous in the lower back of rats. The animals were sacrificed regularly after 3 and 6 months of implantation or when wound defects occurred. The capsules and organs were examined histologically, and immunohistology of the capsules was performed. A monoclonal antibody specific for AIF-1 (allograft inflammatory factor 1) was used to detect activated macrophages. Wound defects occurred most frequently after implantation of saline and hydrogel implants. Increased capsule thickness was associated with increased grade of inflammation, fibrosis, and the type of implant filling. There was a significant positive correlation between capsule thickness, presence of chronic inflammation, and AIF-1-positive macrophages (p < 0.0001), indicating that inflammation plays an important role in capsule formation. Remarkably, saline and silicone implants (in absence of local complications) cause only a blande slight fibrosis in capsules after 6 months of implantation, whereas capsules around cohesive silicone implants exhibited a more severe fibrosis with an increased capsule thickness. Most importantly, hydrogel seems to be most potent to induce an inflammatory infiltrate with AIF-1 expressing macrophages at the implantation site, independent of implantation time, and capsules also produced a significant increase in thickness after 6 months.

Animals↗

PubMed2004

Experimental autoimmune neuritis induces differential microglia activation in the rat spinal cord.

The reactive spatial and temporal activation pattern of parenchymal spinal cord microglia was analyzed in rat experimental autoimmune neuritis (EAN). We observed a differential activation of spinal cord microglial cells. A significant increase in ED1(+) microglia predominantly located in the dorsal horn grey matter of lumbar and thoracic spinal cord levels was observed on Day 12. As revealed by morphological criteria and by staining with further activation markers [allograft inflammatory factor 1 (AIF-1), EMAPII, OX6, P2X(4)R], reactive microglia did not reach a macrophage-like state of full activation. On Day 12, a significant proliferative response could be observed, affecting all spinal cord areas and including ED1(+) microglial cells and a wide range of putative progenitor cells. Thus, in rat EAN, a reactive localized and distinct microglial activation correlating with a generalized proliferative response could be observed.

Animals↗

PubMed2003

Characterisation of a gene cluster in Fugu rubripes containing the complement component C4 gene.

In this study, we describe the characterisation of the complement component C4 gene in Fugu rubripes. The Fugu C4 gene, orthologous to the tetrapod C4 gene, encompasses a genomic span of 9702 base pairs and contains 41 exons, encoding the typical C4 three-chain polypeptide. The gene encodes a protein containing 1703 amino acids. The Fugu C4 protein demonstrates the presence of 25 conserved cysteine residues, as well as conservation of the functionally important thioester site. Complete sequencing of one cosmid and sequence scans from a cluster of 18 overlapping BAC clones, centering around the C4 gene, have identified the short-range linkage with five orthologous human genes mapping to the Major Histocompatibility Complex (MHC) including: tenascin X (TNX); cytochrome P450, subfamily XXIA, polypeptide 2 (CYP21A2); allograft inflammatory factor 1 (AIF1) and casein kinase 2, beta polypeptide (CSNK2B), all found in the MHC class III region; and retinoid X receptor, beta (RXRB),which resides in the MHC extended class II region. To date, this syntenic association of the Fugu C4 and other MHC class III region genes has not been observed in other teleost fish. Data from the recent whole-genome shotgun assemblies reveal the Fugu MHC-related cluster of genes to be flanked predominantly by genes mapping to human chromosomes 7 and 19. All of the six identified Fugu MHC-related genes have been characterised at the genomic level.

Amino Acid Sequence↗

PubMed2004

solution structure, backbone dynamics, and interaction with Cdc42 of Salmonella guanine nucleotide exchange factor SopE2.

SopE and SopE2 are delivered by the Salmonella type III secretion system into eukaryotic cells to promote cell invasion. SopE and SopE2 are potent guanine nucleotide exchange factors (GEFs) for Rho GTPases Cdc42 and Rac1 and constitute a novel class of Rho GEFs. Although the sequence of SopE-like GEFs is not at all homologous to those of the Dbl homology domain-containing eukaryotic GEFs, the mechanism of nucleotide release seems to have significant similarities. We have determined the solution structure of the catalytic domain (residues 69-240) of SopE2, showing that SopE2(69-240) comprises two three-helix bundles (alpha1alpha4alpha5 and alpha2alpha3alpha6) arranged in a Lambda shape. Compared to the crystal structure of SopE(78-240) in complex with Cdc42, SopE2(69-240) exhibits a less open Lambda shape due to movement of SopE(78-240) helices alpha2 and alpha5 to accommodate binding to the Cdc42 switch regions. In an NMR titration to investigate the SopE2(69-240)-Cdc42 interaction, the SopE2(69-240) residues affected by binding Cdc42 were very similar to the SopE(78-240) residues that contact Cdc42 in the SopE(78-240)-Cdc42 complex. Analysis of the backbone (15)N dynamics of SopE2(69-240) revealed flexibility in residues that link the two three-helix bundles, including the alpha3-alpha4 linker that incorporates a beta-hairpin and the catalytic loop, and the alpha5-alpha6 loop, and flexibility in residues involved in interaction with Cdc42. Together, these observations provide experimental evidence of a previously proposed mechanism of GEF-mediated nucleotide exchange based on the Rac1-Tiam1 complex structure, with SopE/E2 flexibility, particularly in the interbundle loops, enabling conformational rearrangements of the nucleotide binding region of Cdc42 through an induced fit type of binding. Such flexibility in SopE/E2 may also facilitate interaction through adaptive binding with alternative target proteins such as Rab5, allograft inflammatory factor 1, and apolipoprotein A-1.

Amino Acid Sequence↗

PubMed2003

Identification of cathepsin B as a mediator of neuronal death induced by Abeta-activated microglial cells using a functional genomics approach.

Alzheimer's disease is a progressive neurodegenerative disease characterized by senile plaques, neurofibrillary tangles, dystrophic neurites, and reactive glial cells. Activated microglia are found to be intimately associated with senile plaques and may play a central role in mediating chronic inflammatory conditions in Alzheimer's disease. Activation of cultured murine microglial BV2 cells by freshly sonicated Abeta42 results in the secretion of neurotoxic factors that kill primary cultured neurons. To understand molecular pathways underlying Abeta-induced microglial activation, we analyzed the expression levels of transcripts isolated from Abeta42-activated BV2 cells using high density filter arrays. The analysis of these arrays identified 554 genes that are transcriptionally up-regulated by Abeta42 in a statistically significant manner. Quantitative reverse transcription-PCR was used to confirm the regulation of a subset of genes, including cysteine proteases cathepsin B and cathepsin L, tissue inhibitor of matrix metalloproteinase 2, cytochrome c oxidase, and allograft inflammatory factor 1. Small interfering RNA-mediated silencing of the cathepsin B gene in Abeta-activated BV2 cells diminished the microglial activation-mediated neurotoxicity. Moreover, CA-074, a specific cathepsin B inhibitor, also abolished the neurotoxic effects caused by Abeta42-activated BV2 cells. Our results suggest an essential role for secreted cathepsin B in neuronal death mediated by Abeta-activated inflammatory response.

Alzheimer Disease↗