Human interleukin‐27: wide individual variation in plasma levels and complex inter‐relationships with interleukin‐17A

Summary Although it is widely believed that interleukin (IL)‐27 is anti‐inflammatory, its role in controlling human immune responses is not fully established. In particular, its interactions with T helper type 17 (Th)17 cytokines are unclear. Our aims were to establish the relationships between IL‐27 and proinflammatory cytokines, including IL‐17A, in human sera and cultures of peripheral blood mononuclear cells. Plasma IL‐27 levels in 879 healthy humans from 163 families varied widely, but with relatively low heritability (19%). Despite IL‐27 including a subunit encoded by Epstein–Barr virus‐induced gene 3 (EBI3), there was no correlation of levels with serological evidence of infection with the virus. Although IL‐27 has been reported to inhibit IL‐17A production, we demonstrated a strong positive correlation in sera, but lower correlations of IL‐27 with other proinflammatory cytokines. We verified that IL‐27 inhibited IL‐17A production by human peripheral blood T cells in vitro, but not that it stimulated IL‐10 secretion. Importantly, addition of IL‐17A decreased IL‐27 production by stimulated T cells but had the opposite effect on resting T cells. Together, these data suggest a model whereby IL‐27 and IL‐17A exerts complex reciprocal effects to boost inflammatory responses, but restrain resting cells to prevent inappropriate activation.