A form of circulating interleukin-6 receptor component soluble gp130 as a potential interleukin-6 inhibitor in inflammatory bowel disease

Mitsuyama, Keiichi; Tomiyasu, Nobuo; Suzuki, Asuka; Takaki, Kosuke; Takedatsu, Hidetoshi; Masuda, Junko; Yamasaki, Hiroshi; Matsumoto, Satoshi; Takahashi, Osamu; Toyonaga, Atsushi; Sata, Michio

doi:10.1111/j.1365-2249.2005.02960.x

Cited by 28 publications

(28 citation statements)

References 48 publications

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“…Solid arrows represent the effects of cholinergic agonists on IL-6 mediated signaling components and downstream events. support the role of nicotine as a regulator of the JAK2/STAT3/ SOCS3 signaling pathway in inflammatory bowel disease (38).…”

Section: Discussionmentioning

confidence: 98%

“…For example, IL-6, STAT3, and SOCS3 have been implicated in inflammatory bowel disease (1,17,39,46) and soluble gp130 has been shown to suppress inflammatory bowel disease (38). Inflammatory bowel disease is a condition that can be treated with the cholinergic agonist nicotine experimentally (59) and clinically (14,16,44,52), as well as with anti-IL-6R antibody (24).…”

Section: Discussionmentioning

confidence: 98%

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Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation

Chatterjee

Al‐Abed

Sherry³

et al. 2009

American Journal of Physiology-Cell Physiology

103

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The cholinergic anti-inflammatory pathway is a physiological mechanism that inhibits cytokine production and minimizes tissue injury during inflammation. Previous investigations revealed that cholinergic stimulation (via cholinergic agonists and vagus nerve stimulation) suppresses endothelial cell activation and leukocyte recruitment. The purpose of this study was to investigate the mechanisms by which cholinergic agonists (e.g., nicotine and GTS-21) regulate endothelial cell activation. Specifically, we examined the effects of cholinergic agonists on IL-6-mediated endothelial cell activation through the JAK2/STAT3 signaling pathway. Treatment of macrovascular human umbilical vein endothelial cells (HUVECs) and microvascular endothelial cells (MVECs) with the cholinergic agonists nicotine and GTS-21 significantly reduced IL-6-mediated monocyte chemoattractant protein-1 (MCP-1) production and ICAM-1 expression which are regulated through the JAK2/STAT3 pathway. We found that treatment of endothelial cells with cholinergic agonists significantly reduced STAT3 activation by phosphorylation and DNA binding. The inhibition of STAT3 phosphorylation was reversed by sodium orthovanadate, an inhibitor of tyrosine phosphatases, as well as by NSC-87877 suggesting a SHP1/2-dependent mechanism. Further investigations showed that cholinergic agonists reduced the phosphorylation of JAK2, an upstream component of the JAK2/STAT3 pathway. Finally, we observed that nicotine and GTS-21 treatment decreased levels of SOCS3 (suppressor of cytokine signaling; a regulator of the inflammatory activity of IL-6) in activated endothelial cells. These data demonstrate that cholinergic agonists suppress IL-6-mediated endothelial cell activation through the JAK2/STAT3 pathway. Our results have significant implications for better understanding the therapeutic potential of cholinergic agonists for treating IL-6 mediated inflammatory conditions.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation

Chatterjee

Al‐Abed

Sherry³

et al. 2009

American Journal of Physiology-Cell Physiology

103

View full text Add to dashboard Cite

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“…IL-6R shedding is therefore an active process within this condition, and sIL-6R required for IL-6-dependent gp130 activation is most likely released either by lamina propria macrophages or infiltrating neutrophils [57,87]. Interestingly, it was recently reported that not only levels of IL-6 but also levels of sIL-6R and sgp130 are elevated in chronic inflammatory bowel diseases and that IL-6 found in the circulation was complexed to sIL-6R and sgp130 [95].…”

Section: Il-6 Trans-signaling In Colitis and Colon Cancermentioning

confidence: 96%

Interleukin-6 and its receptor: from bench to bedside

Scheller

Rose-John

2006

Med Microbiol Immunol

251

208

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Interleukin-6 (IL-6) is an inflammatory cytokine with a well-documented role in inflammation and cancer. The cytokine binds to a membrane bound IL-6 receptor (IL-6R) and this complex associates with two molecules of the signal transducing protein gp130 thereby initiating intracellular signaling. While gp130 is present on most if not all cells of the body, the IL-6R is only present on some cells, mainly hepatocytes and several leukocytes. Cells, which only express gp130 and no IL-6R are refractory to IL-6 signals. We have shown earlier that the IL-6R can exist as a soluble protein generated by limited proteolysis of the membrane bound receptor or by translation from an alternatively spliced mRNA. This soluble IL-6R (sIL-6R) can bind the ligand IL-6 and the soluble complex of sIL-6R and IL-6 can bind to gp130 on cells which lack the membrane bound IL-6R and trigger gp130 signaling. We have named this process 'trans-signaling'. We will review data, which clearly show that IL-6 uses classical signaling via the membrane bound receptor and trans-signaling via the soluble receptor in various physiological and pathophysiological situations. Furthermore, we have developed designer cytokines, which can specifically enhance or inhibit IL-6 trans-signaling. These designer cytokines have been shown to be extremely useful to in therapeutic applications ranging from the long-term culture of stem cells and enhancing liver regeneration up to the blockade of chronic inflammation and cancer.

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“…Increased levels of IL-6, sIL-6R, and soluble gp 130 (sgp130), have been reported in IBD. Thus, the IL-6 trans-signaling pathway may play an important role in the pathogenesis of IBD (Mitsuyama et al 2006b). Studies in CD and experimental colitis have shown that inhibition of IL-6 trans-signaling suppresses T cell resistance to apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD (Atreya et al 2000;Kallen 2002).…”

Section: CDmentioning

confidence: 98%

Spontaneous in vitro IL-6 production in various intestinal segments in patients with inflammatory bowel disease

et al. 2011

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Interleukin-6 (IL-6) plays an important role in regulation of intestinal inflammatory processes in inflammatory bowel disease (IBD). The levels of IL-6 in media from cultured biopsy samples were determined by ELISA in 14 Crohn's disease (CD) patients, 17 patients with ulcerative colitis (UC), and 24 healthy controls in terminal ileum, cecum, and rectum. Results were confirmed by measuring mRNA expression in selected patients. In CD patients, there were increased levels of IL-6 (expressed in picograms per milligram of biopsy tissue mass) in terminal ileum compared with controls (median, 617 vs. 90.4; p < 0.001). High IL-6 levels were found in the rectum of CD patients with active disease but normal endoscopic findings (791 vs. 131; p < 0.05). This result was confirmed by mRNA expression. There was a substantial increase of IL-6 levels in cultured cecal (median, 327 vs. 94.0; p < 0.001) and rectal mucosa (median, 282 vs.131; p < 0.05) but not in ileal mucosa of UC patients. In conclusion, IL-6 production was higher in IBD patients than in controls; it correlated with disease activity and varied among different intestinal segments. In clinically active CD patients without rectal involvement, high IL-6 levels in cultured rectal mucosa suggest immune stimulation even in the absence of macroscopic inflammation.

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A form of circulating interleukin-6 receptor component soluble gp130 as a potential interleukin-6 inhibitor in inflammatory bowel disease

Cited by 28 publications

References 48 publications

Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation

Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation

Interleukin-6 and its receptor: from bench to bedside

Spontaneous in vitro IL-6 production in various intestinal segments in patients with inflammatory bowel disease

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