Signal transducer and activator of transcription 3 (STAT3) and Signal transducer and activator of transcription 1 alpha/beta (STAT1) are phosphorylated after Interleukin-27 (IL27) binds the Interleukin-27 receptor. In Interleukin-2 activated T cells, Interleukin-6 receptor beta subunit (IL6ST, gp130) has STAT3-docking sites, the result of tyrosine phosphorylation by Tyrosine protein-kinase JAK2 (JAK2) and/or Non receptor Tyrosine-protein kinase 2 (TYK2) and JAK1.
In human keratynocytes, Interleukin-12 (IL12) enhanced tyrosine phosphorylation and transcriptional activity of STAT3, possibly mediated by JAK2, which is associated with Interleukin-12 receptor beta 2 subunit (IL12RB2). However Interleukin-23 (IL23) and IL27 did not activate STAT3 in keratinocytes although JAK2 was activated (Kanda & Watanabe 2008)
Inferred from mouse:
As further background, the heterodimeric proteins IL12, IL23 and IL27 activate JAK2 and Non-receptor tyrosine-protein kinase TYK2 (TYK2). IL27 simultaneously activates JAK1. STAT3 is required for IL27 induced up-regulation of c-Myc and Pim-1 and consequent cell proliferation. IL27-induced STAT3 activation is mediated through four tyrosine residues in the YXXQ motif of the cytoplasmic region of IL6ST, as observed with IL6. On the other hand, STAT3 is dispensable for IL27-induced augmentation of Th1 differentiation and IL27 induced supression of proinflammatory cytokine production.
In human keratynocytes IL27 induced both tyrosine phosphorylation and the transcriptional activity of STAT1 in parallel with the activation of JAK1. In IL27-activated naive T cells, the cytoplasmic domain of interleukin-27 receptor alpha subunit (IL27RA, WSX-1) is tyrosine phosphorylated by constitutively associated JAK1, providing a docking site for STAT1 which leads to its phosphorylation and activation by JAK1 (Kanda & Watanabe 2008). Moreover STAT1 silencing in human monocytic THP-1 cells demostrated that IL27 strongly increases STAT1 protein expression. Concomitant with increased STAT1 expression, Interleukin-10 (IL10) induced increased levels of STAT1 tyrosine phosphorylation in monocytes. All of these observations are consistent with results obtained with STAT1-deficient mice, which indicate that STAT1 activation is important for IL27-induced cell proliferation (Owaki et al. 2008).
This is a black box event because the exact mechanism and order of STAT1 and STAT3 binding is unknown.