Autocrine and paracrine cytokine feedback augment the production of Th2-associated cytokines.

Abstract

Abstract The Type 2 cytokines (including cytokines from Th2 and Th9 cells) play a critical role in priming of the humoral response, immunity to parasites, and the induction of allergic disease. It has been proposed that unlike Type 1 cytokines (i.e. IFN-γ), the induction of Type 2 cytokines is cell autonomous and requires no additional signals for optimal cytokine production. Contrary to this notion, we found that the addition of golgi transport inhibitors that block cytokine secretion (i.e. monensin (Mon) and brefeldin A (BFA)) during stimulation significantly impaired the induction of Type 2, but not Type 1 cytokine mRNA and protein production. These data suggest that the release of cytokines by activated Th cells is uniquely required for further production of Type 2 cytokines. Mon and BFA strongly inhibited the release of IL-2 after stimulation and blockade of IL-2 during activation in the absence of golgi inhibitors significantly diminished Type 2 cytokine production. Further, transduction of cells with a constitutively active STAT5 negated the need for additional IL-2 signaling in driving Type 2 cytokine transcription, suggesting that STAT5 is the primary mediator of IL-2-driven gene expression. Interestingly, both autocrine and paracrine IL-2 production were capable of driving maximal Type 2 cytokine production. Taken together, these data indicate a novel role for IL-2 feedback in promoting Type 2 cytokine production and likely in promoting allergic inflammation.