Background/Purpose:  SpA is a chronic inflammatory rheumatic disorder with osteo-articular and extra-articular manifestations. HLA-B27/human β2-microglobulin transgenic rats (B27 rat) spontaneously develop a phenotype closely resembling human SpA and represent an adequate model to better understand the mechanisms involved in SpA development. Disease development in these rats is correlated with accumulation of pro-inflammatory interleukin-17 (IL-17)-producing helper T cells (Th17) and abnormal function of dendritic cells (DCs) which enhance the generation of Th17 cells. Moreover, dysregulated production of IL-17 and IL-10 in favor of IL-17 by regulatory T cells (Treg) was recently described, associated with inducible costimulator (ICOS) overexpression. Transcriptomic study of B27 DCs has revealed a decreased expression of IL-27, an anti-inflammatory cytokine able to decrease IL-17 and increase IL-10 production by T cells. Here, we investigated if addition of exogenous IL-27 would contribute to reverse the pro-inflammatory phenotype of T cells observed in the B27 rats.

Methods: Sorted T cell subsets and sorted CD103+ DCs from B27 rats were co-cultured in the presence or absence of recombinant IL-27. Effector T cells and Tregs were cultured 3 days with coated anti-CD3. Naive T cells were cultured 6 days with coated anti-CD3 in Treg- or Th17-polarizing conditions. Cytokine production was evaluated by intracellular staining after PMA/ionomycin stimulation and by ELISA in the supernatants.

Results:  The addition of exogenous IL-27 inhibited IL-17 expression and increased IL-10 production on several CD4+ T cells subsets, such as effector T cells or Tregs. Moreover, IL-27 inhibited the development of Th17 and promoted IL-10 production from naïve T cells cultured in Treg- or Th17-polarizing conditions. We also observed a downregulation of ICOS expression on T cells cultured in the presence of IL-27. In vitroblockade of IL-10 with a specific antibody demonstrated that this cytokine was not implicated in the modulatory effect of IL-27 on IL-17 production. Moreover, IL-27 still significantly decreased IL-17 production by T cells from B27-ICOS-/- rats, indicating that this effect was also independent of ICOS.

Conclusion: Our results reveal that IL-27 is able to reverse the pro-inflammatory phenotype observed in T cells from B27 rats by reversing the IL-17/IL-10 imbalance in favor of IL-10. Moreover, the effect of IL-27 on IL-17 production was independent of IL-10 and ICOS modulation. Given that IL-17 is a confirmed therapeutic target in SpA, these results suggest that IL-27 may be a new promising therapeutic tool for SpA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/regulation-of-inflammation-by-interleukin-27-in-a-rat-model-of-spondyloarthritis-spa/