The soluble interleukin 6 receptor: mechanisms of production and implications in disease

Jones, Simon A.; Horiuchi, Sankichi; Topley, Nicholas; Yamamoto, Naoki; Fuller, Gerald M.

doi:10.1096/fj.99-1003rev

Cited by 555 publications

(507 citation statements)

References 173 publications

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“…IL-6 signaling can be triggered by two separate pathways [34]. In classical signaling, IL-6 influences cellular responses by binding to a specific IL-6 cell surface receptor subunit (IL-6Rα).…”

Section: Elucidation Of An Il-6 Trans-signaling Mechanismmentioning

confidence: 99%

“…For example, lymphocyte recruitment to areas of inflammation has been linked to an IL-6 trans-signaling mechanism in autoimmune states such as rheumatoid arthritis and inflammatory bowel disease [34]. It is believed that IL-6 trans-signaling also triggers the transition from innate immunity to acquired immunity by selectively regulating chemokine and adhesion molecule-dependent recruitment of leukocyte subsets to inflamed tissues [51].…”

Section: Clinical Implications Of Thermal Therapy Dynamicsmentioning

confidence: 99%

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Primary immune surveillance: some like it hot

et al. 2007

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The thermal element of fever has been found to be beneficial in models of infectious disease. The contributions of fever-range temperatures to the efficacy of the adaptive immune response have only begun to be delineated. There is accumulating evidence that fever-range thermal stress bolsters primary immune surveillance of lymph nodes and Peyer patches by augmenting lymphocyte extravasation across specialized vessels termed high endothelial venules. Molecular mechanisms have recently come to light by which the thermal component of fever alone may promote lymphocyte trafficking, and thereby the probability of mounting a defense against microbial infection. Acquired knowledge of the molecular changes associated with thermal stress may allow for the development of novel therapies for a variety of disease processes.

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Section: Elucidation Of An Il-6 Trans-signaling Mechanismmentioning

confidence: 99%

Section: Clinical Implications Of Thermal Therapy Dynamicsmentioning

confidence: 99%

Primary immune surveillance: some like it hot

et al. 2007

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“…There is compelling evidence that augmented levels of IL-6 are associated with several metabolic diseases, including type 2 diabetes and cardiovascular disease (3)(4)(5)(6). IL-6 acts via a receptor complex consisting of two functional membrane proteins: an 80-kDa ligand-binding IL-6 receptor and a 130-kDa signal transducer (gp130) (7,8). Soluble and active forms of the extracellular domain of the IL-6 receptor, which is produced both by differential splicing of the IL-6 receptor transcript and by proteolytic cleavage of the protein in a process termed shedding, are also found in normal serum and synovial fluids.…”

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confidence: 99%

Interleukin-6 Receptor Gene Variations, Plasma Interleukin-6 Levels, and Type 2 Diabetes in U.S. Women

Rifai

2007

Diabetes

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OBJECTIVE-To examine the associations between common variations in the IL6R gene and circulating interleukin (IL)-6 levels and diabetes risk.RESEARCH DESIGN AND METHODS-We determined 10 linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (SNPs) (SNP1 to SNP10) for the IL6R gene in a nested case-control study of 672 diabetic and 1,058 healthy European Caucasian women (IL-6 levels were measured in a subgroup of 1,348 women).RESULTS-In both control and diabetic patients, polymorphisms within an LD block spanning ϳ42 kb were significantly associated with plasma IL-6 levels. A missense variant SNP7 in exon 9 (rs8192284, Asp358Ala) showed the strongest association (P ϭ 0.0005 in control and P ϭ 0.004 in case subjects). The corresponding false-discovery rates, which accounts for multiple testing, were 0.008 and 0.02, respectively. We inferred five common haplotypes to capture 94% allele variance of the LD block using SNP5, -7, -8, -9, and -10. Compared with the most common haplotype 12111 (one codes the common and two codes the minor alleles), haplotypes 11211 [difference in log(IL-6) ϭ Ϫ0.11 (95% CI Ϫ0.23 to Ϫ0.01); P ϭ 0.01] and 21122 (Ϫ0.15 [Ϫ0.27 to Ϫ0.03]; P ϭ 0.01) were associated with significantly lower IL-6 levels (global test, P ϭ 0.01). However, IL6R genotypes were not significantly associated with the risk of type 2 diabetes.CONCLUSIONS-IL6R genetic variations, especially SNP7 (rs8192284, Asp358Ala), were significantly associated with plasma IL-6 levels but not with diabetes risk in women. The strong associations between IL6R genetic variability and IL-6 concentrations deserve further investigation. Diabetes 56: 3075-3081, 2007

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“…Once bound to IL-6, the resulting IL-6/sIL-6R complex acts as an agonist that is capable of activating cells through gp130. 21 Several studies showed that IL-6/sIL-6R complex could induce proliferation of synovial fibroblastic cells. 50 Moreover, the IL-6/sIL-6R complex has been reported to regulate leukocyte recruitment and to promote proinflammatory stimulation of endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…19 Central to regulation of IL-6-mediated responses is the presence of soluble IL-6 receptor (sIL-6R), which forms a ligand-receptor complex allowing IL-6 responsiveness in cell types not expressing IL-6R. 20,21 This IL-6/sIL-6R complex can activate cells that do not normally respond to IL-6 through interaction with gp130. Although sIL-6R is released into body fluids of normal individuals, high levels of sIL-6R are associated with various diseases [22][23][24][25][26] by promoting a number of biological responses.…”

mentioning

confidence: 99%

Human T‐cell leukemia virus type‐I Tax induces expression of interleukin‐6 receptor (IL‐6R): Shedding of soluble IL‐6R and activation of STAT3 signaling

Horiuchi

Yamamoto

Dewan

et al. 2006

Intl Journal of Cancer

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Human T‐cell leukemia virus type‐I (HTLV‐I) encodes for the viral protein Tax, which is known to significantly disrupt transcriptional control of cytokines, cytokine receptors and other immuno‐modulatory proteins in T cells. Specific dysregulation of these factors can alter the course and pathogenesis of infection. Soluble interleukin‐6 receptor (sIL‐6R) was shown to circulate at elevated levels in HTLV‐I‐infected patients, and high expressions of IL‐6R and sIL‐6R by HTLV‐I‐infected T cells were clinically and experimentally associated with Tax activity. To examine roles of Tax in expression of the IL‐6R gene, the JPX‐9 cell line was used, which is derived from Jurkat cell line expressing Tax cDNA. Over‐expression of Tax enhanced IL‐6R expression but not in Tax mutant JPX‐9/M cell line. The clinical relevance of these observations was further demonstrated by ELISA using sera obtained from HTLV‐I‐infected patients. Our results revealed that sIL‐6R levels were apparently elevated in HAM/TSP patients who were expressing Tax in their cells, while ATL patients' cells barely expressed Tax. HTLV‐I‐infected T‐cell lines stimulated by IL‐6/sIL‐6R showed gp130‐mediated STAT3 activity. IL‐6/sIL‐6R enhanced proliferation of HTLV‐I‐infected T cells in association with activation of STAT3. Consequently, Tax‐mediated regulations of IL‐6R and sIL‐6R observed in HTLV‐I‐associated disorders may contribute to proliferation of HTLV‐I‐infected T cells through activation of inducible STAT3, and ultimately affect malignant growth and transformation of T cells by HTLV‐I. © 2006 Wiley‐Liss, Inc.

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The soluble interleukin 6 receptor: mechanisms of production and implications in disease

Cited by 555 publications

References 173 publications

Primary immune surveillance: some like it hot

Primary immune surveillance: some like it hot

Interleukin-6 Receptor Gene Variations, Plasma Interleukin-6 Levels, and Type 2 Diabetes in U.S. Women

Human T‐cell leukemia virus type‐I Tax induces expression of interleukin‐6 receptor (IL‐6R): Shedding of soluble IL‐6R and activation of STAT3 signaling

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