Background/Purpose:

IL-17A is a Th17 proinflammatory cytokine that contributes to the pathophysiology of several immune-mediated inflammatory diseases including PsA; while previously underestimated, there is increasing evidence supporting a similar proinflammatory role for IL-17F. IL-17E (IL‑25), another IL-17 cytokine, is implicated in Th2 responses, and signals via the IL‑17RA/RB receptor complex, sharing the IL-17RA subunit with IL-17A and IL-17F. Extending upon previous work, we hypothesized that IL-25 indirectly regulates production of Th17 cell cytokines,¹ and a broad range of other inflammatory mediators through effects on polyfunctional T cells. Consequently, selectively targeting IL-17A and IL-17F may offer a therapeutic alternative, in the treatment of immune-mediated inflammatory diseases, to targeting broader signaling pathways by interfering with IL-25. The aim of this study was to investigate the effects of IL-25 on Th17 and polyfunctional T cell responses.

Methods:

Isolated human Th17 cells or peripheral blood mononuclear cells (PBMCs) were either stimulated with Th2 cytokines (IL-4, IL-5 and/or IL-13, IL-25) or Th2-cytokine neutralizing antibodies (10 µg/mL) for 72 hrs, to assess their modulatory effect on Th17 cells in addition to other Th cell subsets. Cytokines in cell supernatant and intracellular cytokines were measured using ELISA and flow cytometry, respectively. To investigate how IL-25 or IL-4 affected polyfunctional T cell responses, PBMCs were stimulated with these cytokines for 72 hrs and intracellular cytokine production was assessed by mass cytometry.

Results:

While IL-25 did not effectively inhibit IL-17A production in stimulated PBMCs, IL-25 did elevate levels of IL-4 in treated versus untreated PBMCs. In contrast to IL-25, IL-4 effectively reduced the percentage of PBMCs expressing IL-17A and IL-17F and inhibited the secretion of IL-17A; the opposite effect was observed using anti-Th2-cytokine antibodies. Both IL-25 and IL-4 inhibited polyfunctional T cell production of the proinflammatory molecules IL-17A, IL-17F, TNF, and IFNγ (Figure 1).

Conclusion: Taken together these data show that IL-25, via IL-4, indirectly modulates IL‑17A and IL-17F production, as well as production of a variety of other proinflammatory molecules (including TNF and IFNγ), through effects on Th17 and polyfunctional T cells. Targeted dual neutralization of IL-17A and IL-17F may therefore produce optimal inhibition of inflammatory signaling responses in immune-mediated inflammatory diseases, without interfering with the regulatory role of IL-25.

¹Liu et al. Sci Rep 2016;6(36002)

Figure 1: IL-4 and IL-25 (10 ng/mL) regulate production of proinflammatory cytokines from polyfunctional T cells.