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PubMed1995

Multiple proteins physically interact with PU.1. Transcriptional synergy with NF-IL6 beta (C/EBP delta, CRP3).

PU.1 is a transcription factor that belongs to the ets family of DNA binding proteins. In this study, we show by Far Western blot analyses that multiple nuclear proteins are capable of physically interacting with PU.1. Using radiolabeled PU.1 protein as a probe, we screened a B cell cDNA expression library and isolated a number of clones encoding PU.1 interacting proteins. Three of these clones encode DNA binding proteins (NF-IL6 beta, HMG I/Y, and SSRP), one clone encodes a chaperone protein, and another clone encodes a multifunctional phosphatase. We have characterized the physical and functional interactions between PU.1 and NF-IL6 beta, a leucine zipper transcription factor implicated in inflammatory responses. We found that deletion of the carboxyl-terminal 28 amino acids of PU.1 disrupted PU.1-NF-IL6 beta physical interaction. This deletion disrupts the PU.1 Ets domain. Deletion of the NF-IL6 beta leucine zipper domain also greatly diminished the interaction between these two proteins. In transient expression assays, we found that PU.1 and NF-IL6 beta can functionally cooperate to synergistically activate transcription. Electrophoretic mobility shift assays showed that PU.1 and NF-IL6 beta can simultaneously bind to adjacent DNA binding sites, but apparently do not influence the kinetics or affinity of each other's DNA binding. These results suggest that transcriptional synergy is due to each protein independently influencing the basal transcription complex.

3T3 Cells↗
PubMed1996

Expression of and response to interleukin 6 (IL6) in human mammary tumors.

Multifunctional cytokines play important and only partially defined roles in mammary tumor development and progression. Normal human mammary epithelia] cells (MECs) constitutively produce interleukin (IL) 6, IL8, and a nonsecreted form of tumor necrosis factor. MEC transformation by different oncogenes is frequently associated with alterations of cytokine/growth factor production and responsiveness. This seems particularly true in the case of IL6. Histochemical studies showed that expression of immunoreactive IL6, as compared to normal tissue and to in situ lesions, is significantly reduced in invasive ductal carcinoma. Conversely, the expression of IL6 in invasive lobular carcinoma was enhanced. Expression of TGF-beta1 in mammary neoplasia was in general less intense than that seen in the normal mammary gland. In vitro studies partially supported the in vivo findings: expression of IL6 and TGF-beta1 was significantly down-regulated in cultures derived from both ductal carcinoma and peritumoral tissue. Similarly, responsiveness to IL6 and TGF-beta1 was significantly reduced in neoplastic MECs. The data suggest that alterations of cytokine pathways are present not only in mammary neoplasia, but also in pathologically unaffected breast tissues.

Breast↗
PubMed1996

Effects of IL-10 and IL-4 on LPS-induced transcription factors (AP-1, NF-IL6 and NF-kappa B) which are involved in IL-6 regulation.

Interleukin-10 (IL-10), like IL-4, is known to inhibit cytokine expression in activated human monocytes. We showed that both IL-10 and IL-4 inhibit LPS-induced IL-6 mRNA and protein expression by inhibiting the transcription rate of the IL-6 gene. The strong inhibition of the IL-6 transcription rate prompted us to study the effect of IL-10 and IL-4 on the expression of transcription factors. We questioned whether or not IL-10 and IL-4 affected the expression of transcription factors that are known to be involved in the control of the IL-6 transcription rate, namely activator protein-1 (AP-1), nuclear factor IL-6 (NF-IL6), and nuclear factor kappa B (NF-kappaB). In electrophoretic mobility shift assays (EMSAs) we showed that IL-10 and IL-4 inhibited LPS-induced AP-1 binding activity. The inhibiting effect of IL-4 was slightly more pronounced than that of IL-10. Downregulation of LPS-induced AP-1 was accompanied, and thus possibly explained, by a reduced expression at mRNA level of the two major components of the AP-1 complex, namely c-fos and c-jun as determined by Northern experiments. Binding activity of NF-IL6 was also strongly inhibited by IL-4 whereas IL-10 showed no effect. NF-IL6 mRNA levels were not affected by IL-10 or IL-4, suggesting that IL-4 affects binding activity of preexisting NF-IL6. Neither IL-10 nor IL-4 inhibited LPS-induced NF-kappa B binding activity. In agreement with this finding, Northern experiments where p65 and p105 mRNA levels were determined, demonstrated that expression of these components of the NF-kappa B transcription factor were not affected by IL-10 or IL-4. Furthermore, neither IL-10 nor IL-4 showed any effect on I-kappa B mRNA expression as determined by Northern experiments. Thus, IL-10 and IL-4 similarly affect IL-6 expression. However, for IL-4 this was accompanied with a reduction of AP-1 and NF-IL6 binding activity whereas IL-10 only inhibited AP-1 binding activity.

Base Sequence↗
PubMed1992

Leukotriene B4 transcriptionally activates interleukin-6 expression involving NK-chi B and NF-IL6.

Leukotriene B4 (LTB4) is a notable participant in inflammation and chemotaxis. It is, however, still unclear whether LTB4 acts in this regard directly or indirectly by stimulating the release of chemotactic and inflammatory cytokines. Here we report that LTB4 induces synthesis of interleukin (IL)-6 by human blood monocytes through transcriptional activation of the IL-6 gene. We furthermore demonstrate that this process involves activation of the transcription factor NF-chi B and, to a lesser extent, of NF-IL6, while the activity of the transcription factor AP-1, shown to otherwise confer IL-6 inducibility, appeared to be unaffected by LTB4. Involvement of NF-chi B and NF-IL6 in induction of IL-6 transcription by monocytes was demonstrated using deleted forms of the IL-6 promoter. Activation of the IL-6 promoter by LTB4 was not only associated with accumulation of the respective transcripts but resulted in synthesis of functional IL-6 protein as well. In addition, LTB4 mediated transactivation of a heterologous promoter construct containing the NF-chi B or the NF-IL6 enhancer, but not the AP-1 enhancer. The signaling events mediating this effect appeared to involve the release of H2O2, since LTB4 failed to induce NF-chi B or NF-IL6 in the presence of the scavenger of H2O2, N-acetyl-L-cysteine.

Binding Sites↗
PubMed2000

Three-hybrid strategy reveals a peptide segment that specifically binds to the 3'-untranslated region of NF-IL6 mRNA.

The 3'UTR of eukaryotic mRNA is an important regulation region, on which many trans factors act. In recent years, a series of 3'UTRs were shown to have tumor suppressor function, including the 3'UTR of the human nuclear factor for interleukin-6 (NF-IL6 3'UTR). To understand molecular basis for this function, we have tried to isolate genes encoding protein factors acting on the RNA of NF-IL6 3'UTR. Here we show that, by using a yeast three-hybrid system, a cDNA fragment was successfully isolated. This cDNA was allowed to express in E. coli, and its expression product, a polypeptide of ca. 70 amino acids long, was shown to specifically bind to the NF-IL6 3'UTR RNA. A search in GenBank did not reveal homologous sequences. Therefore, this cDNA fragment may be a part of the gene of a novel NF-IL6 3'UTR specific binding protein.

Amino Acid Sequence↗
PubMed1997

CSF-1-induced and constitutive Il6 gene expression in mouse macrophages: evidence for PKC-dependent and -independent pathways.

It has been recently shown that CSF-1 enhanced the constitutive expression of the Il6 gene in resident mouse peritoneal macrophages (PM phi) but little is known about the pathways involved. In this report, we show that both constitutive and CSF-1-induced IL-6 release were enhanced and prolonged in the presence of the PKC inhibitors, staurosporine (SP) and its derivative, GF-109203X. Enhancement of constitutive IL-6 release required higher concentrations of inhibitors, while enhanced CSF-1-induced release was diminished when inhibitor concentrations exceeded defined limits. SP was also shown to activate constitutive IL-6 release by blood monocytes and elicited PM phi but had no effect on their responsiveness to CSF-1. Activation of PKC by exposure of resident PM phi to phorbol myristate acetate (PMA) also resulted in enhanced IL-6 release and PMA was shown to synergize with CSF-1. These data indicate that CSF-1 does not induce Il6 gene expression by amplifying the constitutive pathway in all mononuclear phagocyte subpopulations. It exerts its effects independently of PKC, which may activate Il6 gene expression in its own right by an alternative pathway. While CSF-1 and PKC are involved in separate pathways, the synergistic IL-6 response seen when PMA and CSF-1 interact suggests convergence of the two pathways. It is also apparent that multiple PKs, excluding PKC, may be involved in repressing constitutive and CSF-1-induced Il6 gene expression.

Animals↗
PubMedDate not supplied

Release of TNF alpha and IL6 from human monocytes infected with Mycobacterium kansasii: a comparison to Mycobacterium avium.

Tumor necrosis factor alpha (TNF alpha) and interleukin 6 (IL6) are cytokines with a varied spectrum of inflammatory and immunological activities, for example modulation of acute phase proteins, fever and stimulation of B-lymphocytes. Mycobacterium avium has been shown to stimulate the release of TNF alpha and IL6 from cultured human monocytes and macrophages into the cell supernatant. Cultured human monocytes were infected with Mycobacterium kansasii and M. avium. The concentrations of TNF alpha and IL6 were measured in the supernatant. Monocytes infected with M. kansasii produced significantly lower amounts of TNF alpha (34.8 +/- 20.3 pg/ml) and IL6 (12.0 +/- 8.9 pg/ml) compared to monocytes infected with M. avium (198.3 +/- 171.7 pg/ml and 63.2 +/- 37.6 pg/ml respectively). The extent of cytokine production might be relevant for the clinical manifestation of mycobacterial disease.

Adult↗
PubMed1992

Streptococcal-related antigens stimulate production of IL6 and interferon-gamma by T cells from patients with Behcet's disease.

Greater attention has been recently paid to the role of certain strains of streptococcus as an etiologic agent of Behçet's disease, in which T cell abnormalities are considered to be involved. We therefore examined whether T cells from patients with Behçet's disease might to be stimulated by Streptococcus sanguis-related antigen (RRE KTH-1 antigens). T cells from 17 patients with Behcet's disease, but not those from 13 healthy individuals or from 13 patients with other rheumatic diseases, were stimulated to produce greater amounts of interleukin 6 (IL6) by addition of RRE KTH-1 antigens [stimulation index: 3.96 +/- 0.56 and 1.35 +/- 0.28 or 1.83 +/- 0.43 (mean +/- SEM), respectively]. The IL6 production by T cells required the presence of either fresh or paraformaldehyde-fixed monocytes. The enhancement of T cell IL6 production was not related to the presence of HLA-B51, which has been shown to be frequently associated with Behçet's disease. These results indicate that T cells from patients with Behçet's disease are stimulated by streptococcal antigens to produce IL6 through T cell-monocyte interactions in which binding of the antigens to monocytes, but not necessarily processing of the antigens by monocytes, is involved. Moreover, RRE KTH-1 antigens as well as Escherichia coli-derived antigens also enhanced the production of interferon-gamma by T cells from patients with Behçet's disease. The data thus suggest that T cell hypersensitivity to several bacterial antigens may play a central role in the pathogenesis of Behçet's disease.

Adult↗
PubMed2004

Acute SIV infection of the brain leads to upregulation of IL6 and interferon-regulated genes: expression patterns throughout disease progression and impact on neuroAIDS.

The virus/host interactions during the acute phase of human immunodeficiency virus (HIV) infection help determine the course of disease. During this time period, virus enters the brain. Here, we report clusters of genes whose transcripts are significantly upregulated in the frontal lobe of the brain during acute simian immunodeficiency virus (SIV) infection of rhesus monkeys. Many of these genes are involved in interferon (IFN) and/or interleukin (IL)-6 pathways. Although neither IFNalpha nor IFNgamma are elevated in the brain, IL6 is increased. Both IFNalpha and IL6 are elevated in plasma during this acute phase. The upregulation of STAT1, verified by immunohistochemical staining, can be due to both central nervous system (CNS) (SIV and IL6) and peripheral (IFNalpha and IL6) causes, and can itself drive the expression of many of these genes. Examination of the levels of expression of the upregulated genes in the post-acute and long-term phases of infection, as well as in SIV encephalitis, reveals increased expression throughout SIV infection, which may serve to protect the brain, but can have untoward long-term consequences.

Analysis of Variance↗
PubMed2004

Haplotype structure of inflammatory cytokines genes (IL1B, IL6 and TNF/LTA) in US Caucasians and African Americans.

The major inflammatory cytokines interleukin(IL)1beta, IL6 and tumor necrosis factor alpha (TNFalpha) play a crucial role in infection, inflammation and stress responses. Previously, three coding genes were resequenced, identifying promoter polymorphisms that were used in association studies of neurodegenerative diseases, metabolic disorders and cancer. These studies have produced intriguing but inconsistent results, potentially because the known functional variants: IL1B-511 C>T, IL6-174 G>C and TNF-308 G>A provided an incomplete picture of the total functional diversity at these genes. Therefore, we created marker panels for IL1B, IL6 and TNF/LTA that included the known functional marker but also other markers evenly spaced and with sufficient density to identify haplotype block structure and to maximize haplotype diversity. A total of 26 markers were genotyped in 96 US Caucasians and 96 African Americans. In both populations, a single block with little evidence of historical recombination was observed in IL1B, IL6 and TNF/LTA. For each gene, haplotypes captured the information content of each functional locus, even if that locus was not genotyped, and presumably haplotypes would capture the signal from unknown functional loci whose alleles are of moderate abundance. This study demonstrates the utility of using gene haplotype maps and marker panels as tools for linkage studies on related phenotypes.

Black or African American↗
PubMed1998

Interleukin (IL)-1 and IL-4 synergistically stimulate NF-IL6 activity and IL-6 production in human mesangial cells.

BACKGROUND: While interleukin (IL)-4 inhibits pro-inflammatory cytokine expression by human monocytes, we have observed that it potentiates IL-6 production by IL-1-activated human mesangial cells (MC). To study the mechanism of this cell-type specific interaction between IL-1 and IL-4 in MC, we examined the effect of both cytokines on the activities of nuclear factor kappa B (NF-kappa B) and nuclear IL-6 NL-IL 6), transcription factors that are essential for IL-6 gene expression. METHODS: We evaluated IL-6 synthesis, mRNA expression, and mRNA stability by ELISA, Northern analysis, and the actinomycin D method, respectively. Activities of NF-kappa B and NF-IL 6 were analyzed by gel shift assay. RESULTS: IL-4 augmented the IL-1 stimulated IL-6 mRNA levels by about threefold without altering mRNA stability. IL-1 treatment rapidly induced the binding activity of NF-kappa B. In contrast, IL-4 did not affect basal and IL-1-induced NF-kappa B activities. Both IL-1 and IL-4 stimulated NF-IL6 activity as early as 30 minutes after treatment. When MC were treated with both cytokines together, marked activation of NF-IL6 was observed at five hours. CONCLUSIONS: These results suggest that simultaneous activation of NF-kappa B and NF-IL6 is essential for IL-6 gene expression and that IL-1 and IL-4 cooperatively stimulate MC IL-6 production through their synergistic activation of NF-IL6.

CCAAT-Enhancer-Binding Proteins↗
PubMed1996

Retinoblastoma protein directly interacts with and activates the transcription factor NF-IL6.

The biological function of the retinoblastoma protein (RB) in the cell division cycle has been extensively documented, but its apparent role in differentiation remains largely unexplored. To investigate how RB is involved in differentiation, the U937 large-cell lymphoma line was induced to differentiate along a monocyte/macrophage lineage. During differentiation RB was found to interact directly through its simian virus 40 large tumor antigen (T antigen)-binding domain with NF-IL6, a member of the CAAT/enhancer-binding protein (C/EBP) family of transcription factors. NF-IL6 utilizes two distinct regions to bind to the hypophosphorylated form of RB in vitro and in cells. Wild-type but not mutant RB enhanced both binding activity of NF-IL6 to its cognate DNA sequences in vitro and promoter transactivation by NF-IL6 in cells. These findings indicate a novel biochemical function of RB: it activates, by an apparent chaperone-like activity, specific transcription factors important for differentiation. This contrasts with its sequestration and inactivation of other transcription factors, such as E2F-1, which promote progression of the cell cycle. Such disparate mechanisms may help to explain the dual role of RB in cell differentiation and the cell division cycle.

Amino Acid Sequence↗
PubMed2002

Effects of vomitoxin (deoxynivalenol) on the binding of transcription factors AP-1, NF-kappaB, and NF-IL6 in raw 264.7 macrophage cells.

The effects of vomitoxin (VT) on the binding activity of three transcription factors critical to pro-inflammatory cytokine regulation were assessed in the RAW 264.7 murine macrophage model by electrophoretic mobility shift assay (EMSA). When cells were treated with 100 to 250 ng/ml of VT, activator protein-1 (AP-1 binding) was increased after 2 and 8 h. This effect was potentiated when cells were coincubated with lipopolysaccharide (LPS) (synchronous model) but not when preincubated with LPS (delayed synchronous model). Supershift EMSA revealed that VT preferentially induced JunB, JunD, phosphorylated c-Jun, c-Fos, and Fra-2 binding activities of the AP-1 family. Nuclear factor kappaB (NF-kappaB) binding was increased at 2 and 8 h in cells subjected to synchronous and delayed synchronous VT exposure in the presence of LPS. Supershift EMSA indicated that the p-50 and c-Rel subunits of NF-kappaB/ Rel were specifically affected. Nuclear factor-IL6 (NF-IL6) binding was increased at 2 and 8 h with or without LPS in synchronous and delayed synchronous VT-exposure models. Here, the C/EBPbeta subunit was primarily involved in enhanced NF-IL6 binding. The capacity of VT to elevate binding of AP-1, NF-kappaB, and NF-IL6 may contribute to the VT-mediated cytokine up-regulation in vitro and in vivo. The observations that VT was active in synchronous and delayed synchronous models suggest that macrophages activated simultaneously or prior to toxin exposure were vulnerable to the effects of this trichothecene.

Animals↗
PubMed1993

Regulation of the interleukin-1 beta (IL-1 beta) gene by mycobacterial components and lipopolysaccharide is mediated by two nuclear factor-IL6 motifs.

The cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) are released by mononuclear phagocytes in vitro after stimulation with mycobacteria and are considered to mediate pathophysiologic events, including granuloma formation and systemic symptoms. We demonstrated that the Mycobacterium tuberculosis cell wall component lipoarabinomannan (LAM) is a very potent inducer of IL-1 beta gene expression in human monocytes and investigated the mechanism of this effect. We localized the LAM-, lipopolysaccharide (LPS)-, and TNF-alpha-inducible promoter activity to a -131/+15 (positions -131 to +15) DNA fragment of the IL-1 beta gene by deletion analysis and chloramphenicol acetyltransferase assay. Within this DNA fragment, there were two novel 9-bp motifs (-90/-82 and -40/-32) with high homology to the nuclear factor-IL6 (NF-IL6) binding site. Site-directed mutagenesis demonstrated that the two NF-IL-6 motifs could be independently activated by LAM, LPS, or TNF-alpha and that they acted in an orientation-independent manner. DNA mobility shift assay revealed specific binding of nuclear protein(s) from LAM-, LPS-, or TNF-alpha-stimulated THP-1 cells to the NF-IL6 motifs. We conclude that the two NF-IL6 sites mediate induction of IL-1 beta in response to the stimuli LAM, LPS, and TNF-alpha.

Base Sequence↗
PubMed2002

Addition of interleukin 1 (IL1) and IL17 soluble receptors to a tumour necrosis factor alpha soluble receptor more effectively reduces the production of IL6 and macrophage inhibitory protein-3alpha and increases that of collagen in an in vitro model of rheumatoid synoviocyte activation.

OBJECTIVES: To evaluate the usefulness of combination treatment with cytokine inhibitors. METHODS: A simplified model was set up to evaluate the effect of tumour necrosis factor alpha (TNFalpha) soluble receptors (sTNFR) used alone and in combination with soluble interleukin 1 receptor (sIL1R) and sIL17R on the production of markers of inflammation (IL6), of migration of dendritic cells (macrophage inhibitory protein-3alpha (MIP-3alpha)), and of matrix synthesis (C-propeptide of type 1 collagen (P1CP)). Synoviocytes were stimulated with supernatants of activated peripheral blood mononuclear cells (PBMC) from patients with rheumatoid arthritis (RA). Soluble receptors (sR) were preincubated at 1 gammag/ml alone or in combination with the supernatants before addition to RA synoviocytes. IL6, MIP-3alpha, and P1CP production was measured by enzyme linked immunosorbent assay (ELISA) in 48 hour synoviocyte supernatants. RESULTS: IL6 production decreased by 16% with sTNFR alone compared with no sTNFR (p<0.001) and by 41% with the combination of the three sR (p<0.001). MIP-3alpha production decreased by 77% with sTNFR alone compared with no sTNFR (p<0.001) and by 98% with the combination of the three sR (p<0.001). In the presence of sTNFR alone, P1CP production increased by 25% compared with no sR (p<0.01). The combination of the three sR increased P1CP production by 48% (p<0.01). CONCLUSION: The effect of sTNFR on IL6, MIP-3alpha, and P1CP production by RA synoviocytes stimulated by activated PBMC supernatants was further enhanced when combined with sIL1R and sIL17R.

Adult↗
PubMed1999

Calcium channel blockers activate the interleukin-6 gene via the transcription factors NF-IL6 and NF-kappaB in primary human vascular smooth muscle cells.

BACKGROUND: Calcium channel blockers (CCB) of all subclasses: the dihydropyridines, benzothiazepines, and phenylalkylamines, at nanomolar concentrations, have been shown to up-regulate interleukin-6 (IL-6) mRNA. We investigated the underlying molecular mechanism responsible for IL-6 induction in response to the CCB amlodipine, diltiazem, and verapamil in primary human vascular smooth muscle cells (VSMC). METHODS AND RESULTS: All 3 CCB directly activated transcription of the human IL-6 gene in primary human VSMC in a time- and dose-dependent manner, as demonstrated by luciferase reporter gene assays using a 651-bp fragment of the human IL-6 gene promoter. Deletion analysis of the IL-6 promoter revealed that CCB inducible promoter activity was localized to a 160-bp fragment directly upstream of the transcriptional start site of the IL-6 gene. Known transcription factor consensus sequences within this fragment include a NF-IL6 and a NF-kappaB site. Site-directed mutagenesis suggested that both transcription factors had positive regulatory activity and cooperatively transmitted induction of the IL-6 gene by CCB. The data are confirmed by electrophoretic mobility shift analyses using nuclear extracts from CCB-stimulated and control primary VSMC. CCB of all subclasses increased DNA binding of NF-IL6 and NF-kappaB as early as 30 minutes after stimulation with the drugs. This effect was independent of intracellular calcium concentrations because calcium-free medium did not increase NF-IL6 or NF-kappaB activity. CONCLUSIONS: The results demonstrate that CCB of all 3 subclasses are capable of activating NF-IL6 and NF-kappaB. CCB may thus directly regulate cellular functions by affecting the activity of transcription factors independent of changes of intracellular calcium concentrations, an observation that is of interest considering the biological effects induced by CCB.

CCAAT-Enhancer-Binding Proteins↗
PubMed1994

Expression of mRNA for IL1 beta, IL6 and TGF beta 1 in developing human bone and cartilage.

Using in situ hybridization, we investigated the expression of mRNA for interleukin-1 beta (IL1 beta), interleukin-6 (IL6), and transforming growth factor-beta-1 (TGF beta 1) in sections of developing bone in human osteophytes. The expression was related to the cellular activity of alkaline phosphatase to aid in the identification of pre-osteoblast populations. IL1 beta mRNA was localized in active osteoblasts within distinct areas of intramembranous ossification. However, the expression was sporadic and appeared to occur at a specific stage of the osteoblast life cycle. There was no IL1 beta mRNA expression in any cell types during endochondral ossification. IL6 mRNA expression was located within pre-osteoblasts and in newly differentiated and matrix-secreting osteoblasts; expression was absent or reduced in flattened, inactive osteoblasts. Weak or no IL6 expression was observed in chondroblasts and chondrocytes, respectively. However, there was a close association between IL6 mRNA expression and the differentiation of mesenchymal cells into osteoblasts. TGF beta 1 expression was localized to osteoblasts apposed to bone or cartilage matrix; the intensity of expression correlated with matrix secretion. Chondroblasts and chondrocytes expressed lower but significant levels of TGF beta 1 mRNA; the expression was lost with the progression to calcifying cartilage. The three cytokines studied were differentially expressed both temporally and spatially, suggesting different roles for each in osteoblast and chondrocyte function.

Alkaline Phosphatase↗
PubMed2000

An IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in men infected with human immunodeficiency virus.

Kaposi sarcoma (KS) is an angioproliferative inflammatory condition that occurs commonly in patients infected with human immunodeficiency virus (HIV). Inflammatory cytokines and growth factors promote the development of KS. Because physiologically important cytokine polymorphisms modulate host inflammatory responses, we investigated the association between KS and common regulatory polymorphisms in 5 proinflammatory cytokine genes encoding interleukin (IL) IL-1alpha, IL-1beta, tumor necrosis factor (TNF) alpha, TNF-beta, and IL-6 and in the IL-1 receptor antagonist (IL1RN). We also examined the contribution of stromal-derived factor 1 and chemokine receptor 5 (Delta32) polymorphisms to KS development. The population consisted of 115 HIV-infected men with KS and 126 deceased HIV-infected men without KS. The only strong association was observed between an IL6 promoter polymorphism (G-174C) and susceptibility to KS in HIV-infected men (P =.0035). Homozygotes for IL6 allele G, associated with increased IL6 production, were overrepresented among patients with KS (P =.0046), whereas allele C homozygotes were underrepresented (P =.0062). Substantial in vitro evidence indicates that IL-6 contributes to the pathogenesis of KS. Our results show that IL6 promoter genotypes associated with altered gene expression are risk factors for development of KS. Identification of a genetic risk factor for development of KS has important clinical implications for prevention and therapy.

Alleles↗