Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
The immunological roles of interleukin 27 (IL-27) have been reported in various rheumatic diseases, such as rheumatoid arthritis (RA), lupus, systemic sclerosis and psoriasis. The role of IL-27 in the immune response is not fully understood, although pro- and anti-inflammatory responses to IL-27 were reported. IL-27 is a heterodimeric cytokine composed of IL-27p28 and EBI3, which are analogous to IL-6 and soluble IL-6 receptor (sIL-6R) respectively, and exerts its biological activities through binding to IL-27 receptor which is composed of alpha subunit and gp130. Since IL-6 and IL-27 are similar in terms of their structures and the way of signaling pathway, we hypothesized that sIL-6R binds to IL-27. In this study, we investigated a possible role of sIL-6R in regulating IL-27 signaling.
Methods:
Surface Plasmon Resonance (SPR) analysis was used to examine the binding of IL-27 to sIL-6R. CD14+ cells were isolated from peripheral blood of RA patients. CD14+ cells were incubated with IL-27, sIL-6R and anti-gp130 antibody for 30 minutes, and the expression of SOCS3, which is a negative regulator of inflammatory cytokine signaling, was measured by western blotting. MCP-1 was measured by ELISA in the culture supernatant of CD14+ cells incubated with M-CSF, TNF-α, IL-27, sIL-6R, anti-IL-6 antibody, anti-IL-6R antibody (tocilizumab) and anti-gp130 antibody. The number of osteoclasts was counted after tartrate-resistant acid phosphatase staining in CD14+cells cultured with RANKL and M-CSF in the presence of IL-27, sIL-6R and tocilizumab for 4 days.
Results:
SPR analysis showed that binding curves were generated from experiments in which IL-27 was exposed to a high-density of sIL-6R coated on a sensor chip, showing that IL-27 bound to sIL-6R. IL-27 induced the expression of SOCS3 in CD14+ cells, which was suppressed by the addition of sIL-6R to the culture. Neutralizing antibody to gp130 restored the suppression of the expression of SOCS3 by sIL-6R. Whereas IL-27 reduced MCP-1 production by CD14+ cells stimulated with TNF-α, further addition of sIL-6R restored the production of MCP-1. To clarify which units are important for transducing signal, tocilizumab and an anti-gp130 antibody, but not an anti-IL-6 antibody, inhibited TNF-α-induced MCP-1 production in the presence of IL-27 and sIL-6R. Similarly, RANKL-mediated osteoclast formation was suppressed by IL-27, and sIL-6R antagonized the activity of IL-27. Tocilizumab inhibited osteoclastgenesis in CD14+ cells cultured with IL-27 in the presence of sIL-6R.
Conclusion:
Our results suggest that sIL-6R binds to IL-27, antagonizes the IL-27 signaling, and blocks IL-27-mediated anti-inflammatory effects through gp130. In addition, tocilizumab, but not an anti-IL-6 antibody rescued IL-27-mediated anti-inflammatory effects in the presence of sIL-6R. These data suggest that sIL-6R may be involved in modulating the anti-inflammatory responses of IL-27.
Disclosure:
M. Hashizume,
Chugai Pharmaceutical Co., Ltd,
3;
K. Esaki,
Chugai Pharmaceutical Co., Ltd,
3;
K. Yoshimoto,
None;
H. Kameda,
None;
T. Takeuchi,
Abbott, Abbvie, Asahi Kasei, Astellas, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Pfizer, Sanofi-aventis, Santen, Taisho-Toyama, Takeda, and Teijin,
2,
Asahi Kasei, Abbvie, Daiichi-Sankyo, AstraZeneca, Eli Lilly, Novartis, and Mitsubishi-Tanabe,
5,
Abbott, Astellas, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer, and Takeda,
8;
Y. Matsumoto,
Chugai Pharmaceutical Co., Ltd.,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-function-of-soluble-interleukin-6-receptor-as-an-antagonist-of-interleukin-27-mediated-anti-inflammatory-responses/