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THU0383 Aberrant Expression of Novel Pro-Inflammatory Cytokine Interleukin-36 in Patients with Systemic Lupus Erythematosus: A Cross-Sectional Study
  1. M. Chu1,
  2. C.K. Wong1,
  3. L.S. Tam2
  1. 1Department of Chemical Pathology
  2. 2Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China

Abstract

Background 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.

Objectives The aim of this study was to elucidate IL-36 mediated inflammatory mechanism in patients with systemic lupus erythematosus (SLE).

Methods 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+IL-22+IL-17+ T helper (Th) 17 and CD19+CD24highCD27+ regulatory B (Breg) cells were analyzed by flow cytometry. Ex vivo production of cytokines/chemokines from peripheral blood mononuclear cells (PBMC) cultured with recombinant IL-36 were determined by Luminex multiplex assay.

Results Plasma concentrations of IL-36α, IL-36γ (both p <0.01) and IL-36R (p <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+ B cells in moderate and severe SLE patients compared with NC (both p <0.05). The frequency of circulating Th17 cells was significantly higher in moderate (p<0.001) and severe (p<0.01) SLE patients compared with NC. The frequency of circulating Breg cells was significantly decreased in patients with mild, moderate (both p <0.01) and severe (p <0.001) SLE, and correlated negatively with plasma IL-36γ concentration. In NC, ex vivo production of IL-1β, IL-6, CXCL8, CCL2 (all p <0.001) and IL-10 (p <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 p <0.05).

Conclusions 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 ex vivo 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+ 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.

References

  1. 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.

  2. 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.

Acknowledgements 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).

Disclosure of Interest None declared

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