THU0383 Aberrant Expression of Novel Pro-Inflammatory Cytokine Interleukin-36 in Patients with Systemic Lupus Erythematosus: A Cross-Sectional Study
Authors: M. Chu, C.K. Wong, L.S. Tam
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Interleukin (IL)-36 is a novel inflammatory member of the IL-1 cytokine family comprising three different isoforms: IL-36α, IL-36β and IL-36γ. <h3>Objectives</h3> The aim of this study was to elucidate IL-36 mediated inflammatory mechanism in patients with systemic lupus erythematosus (SLE). <h3>Methods</h3> Forty-five Chinese SLE patients and fifteen age- and sex- matched normal controls (NC) were recruited in rheumatology clinic, Prince of Wales Hospital, Hong Kong. Ethics approval has been obtained from Ethics Committee of The Chinese University of Hong Kong-New Territories East Cluster Hospitals.The expression pattern of IL-36 and its putative receptors of peripheral blood were studied using ELISA and flow cytometry. The frequencies of circulating CD3<sup>+</sup>IL-22<sup>+</sup>IL-17<sup>+</sup> T helper (Th) 17 and CD19<sup>+</sup>CD24<sup>high</sup>CD27<sup>+</sup> regulatory B (Breg) cells were analyzed by flow cytometry. <i>Ex vivo</i> production of cytokines/chemokines from peripheral blood mononuclear cells (PBMC) cultured with recombinant IL-36 were determined by Luminex multiplex assay. <h3>Results</h3> Plasma concentrations of IL-36α, IL-36γ (both <i>p</i> &lt;0.01) and IL-36R (<i>p</i> &lt;0.05) were significantly increased in severe SLE patients compared with NC. All three parameters correlated positively with SLE disease activity index (SLEDAI), while IL-36γ and IL-36R correlated negatively with serum complement C4 concentration. The expression of IL-36R was significantly upregulated on the IL-36R<sup>+</sup> B cells in moderate and severe SLE patients compared with NC (both <i>p</i> &lt;0.05). The frequency of circulating Th17 cells was significantly higher in moderate (<i>p</i>&lt;0.001) and severe (<i>p</i>&lt;0.01) SLE patients compared with NC. The frequency of circulating Breg cells was significantly decreased in patients with mild, moderate (both <i>p</i> &lt;0.01) and severe (<i>p</i> &lt;0.001) SLE, and correlated negatively with plasma IL-36γ concentration. In NC, <i>ex vivo</i> production of IL-1β, IL-6, CXCL8, CCL2 (all <i>p</i> &lt;0.001) and IL-10 (<i>p</i> &lt;0.05), but not Th1 cytokine interferon-γ, was significantly higher following treatment of IL-36β compared with medium control. Upon the stimulation with IL-36α and IL-36γ, production of IL-1β, IL-6, CXCL8 and IL-10 was significantly increased in SLE patients compared with NC (all <i>p</i> &lt;0.05). <h3>Conclusions</h3> Elevated plasma IL-36α, IL-36γ and IL-36R concentrations in SLE patients was found to correlate positively with SLE disease severity, and IL-36 exerted a proinflammatory effect on <i>ex vivo</i> PBMC culture by inducing the production of several cytokines/chemokines. The failure of inducing Th1 cytokine IFN-γ production may possibly be due to the absence of IL-36R on human CD4<sup>+</sup> Th cells, whereas, to our surprise, there are about twenty percent of B cells expressing IL-36R in SLE patients. This cross-sectional clinical study demonstrated a possible pathogenic role of IL-36 in human SLE. <h3>References</h3> Vigne S, Palmer G, Martin P, et al. IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of naive CD4+ T cells. Blood 2012, 120(17):3478-3487. Vigne S, Palmer G, Lamacchia C, et al. IL-36R ligands are potent regulators of dendritic and T cells. Blood 2011, 118(22):5813-5823. <h3>Acknowledgements</h3> We thank Ms Michelle OY Pui and Ms Angela PY Yung for their efforts on the collection and logistics of clinical samples. Funding: this work was supported by the Hong Kong Society of Rheumatology Project Fund (2013-2014). <h3>Disclosure of Interest</h3> None declared