Background/Purpose

The immunological roles of interleukin 27 (IL-27) have been reported in the function of regulatory T cells (Treg), monocytes and osteoclasts, and these cells are involved in various autoimmune diseases, such as rheumatoid arthritis (RA), lupus, systemic sclerosis, and psoriasis. There was a paucity of information about how the function of IL-27 is regulates in autoimmune disease. 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. In this study, we investigated whether a possible role of sIL-6R in regulating IL-27 function.

Methods

CD14⁺ cells were isolated from peripheral blood in RA patients. MCP-1 was measured by ELISA in the culture supernatant of incubated with TNF-α, IL-27, sIL-6R, anti-IL-6 antibody and anti-IL-6R antibody (tocilizumab). In the experiments of osteoclasts, CD14⁺cells were cultured with RANKL and M-CSF in the presence of IL-27, sIL-6R, anti-IL-6 antibody and tocilizumab for 4 days and the number of osteoclasts was counted . Consecutive RA patients who received 8mg/kg of tocilizumab every 4 weeks as first biologics between March 2010 and April 2012 after giving a written informed consent were included in this study (n=39). The proportions of Treg and monocytes at base line, week 24 and week 52 were sequentially measured by using the expression levels of differentiation markers, activation markers and co-stimulatory molecule markers in T cells and monocytes defined in previous report.

Results

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 is an important unit either IL-6 or sIL-6R for modulating IL-27 function, we measured MCP-1 production in the presence of anti-IL-6 antibody or tocilizumab. Tocilizumab, but not an anti-IL-6 antibody, inhibited TNF-α-induced MCP-1 production in the presence of IL-27 and sIL-6R. RANKL-mediated osteoclast formation was suppressed by IL-27, and sIL-6R antagonized the activity of IL-27. Tocilizumab, but not anti-IL-6 antibody inhibited osteoclastgenesis in the presence of IL-27 and sIL-6R. Over the treatment with tocilizumab, the proportions of Treg and HLA-DR⁺ activated Treg were significantly increased from baseline (Treg: p=0.0034, activated Treg: p=0.0008 by Wilcoxon rank test). The proportions of HLA-DR⁺CD14⁺ activated monocytes, CD69⁺CD14⁺ activated monocytes and CD16⁺CD14⁺ non-classical monocytes were significantly decreased from baseline to 52 weeks after treatment (HLA-DR⁺ activated monocytes: p=0.0006, CD69⁺activated monocytes: p<0.0001, non-classical monocytes: p<0.0001).

Conclusion

Our results suggest that sIL-6R antagonizes the IL-27 signaling, and blocks IL-27-mediated anti-inflammatory effects. In addition, tocilizumab, but not an anti-IL-6 antibody rescued IL-27-mediated anti-inflammatory effects in the presence of sIL-6R. And in vivo study demonstrates that tocilizumab showed differential effects on the proportions of circulating Treg and monocytes in RA patients. These data suggest that tocilizumab may be involved in modulating the anti-inflammatory responses of IL-27.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-function-of-tocilizumab-as-a-modulator-of-interleukin-27-mediated-anti-inflammatory-responses/