Interleukin-33 promotes type 1 cytokine expression via p38 MAPK in human natural killer cells

David E. Ochayon; Ayad Ali; Pablo C. Alarcon; Durga Krishnamurthy; Leah C. Kottyan; Michael Borchers; Stephen N. Waggoner

The type 1 cytokine, IL-18, enhances expression of IFNG by IL-12-stimulated human NK cells 30 in part via p38 MAPK stabilization of IFNG transcripts 23 . Our data suggest that a type 2 cytokine, IL-33, similarly enhances IL-12-induced IFN- expression by human NK cells. Moreover, IL-33 amplification of IFN- is dependent on p38 MAPK activity and associated with increased stability of IFNG mRNA. The p38 MAPK regulates inflammatory responses via phosphorylation of downstream mediators, including MK2 31, 32 . Yet, MK2 inhibitors had only a partial inhibitory effect in contrast to the abrogation of IL-12/IL-33 synergistic interactions following p38 MAPK inhibition. This finding implies that other p38 MAPK-stimulated mediators, including ATF2, may also be crucial for the enhancing effect of IL-33. In fact, IL-33 rapidly induced the phosphorylation of p38 MAPK and ATF2 in human NK cells. Of note, p38 MAPK-induced activation of ATF2 initiates activator protein 1 (AP-1) complex-mediated transcription of inflammatory cytokines, including IFN- [33] [34] [35] . Coupled with the lack of apparent effects of IL-33 on IL-12-induced phosphorylation of STAT4, our results highlight the possibility that IL-33 enhances IFN- via enhanced AP-1dependent promotion of transcription.