IL-18 and IL-12 signal through the NF-κB pathway to induce NK-1R expression on T cells

Substance P engages the T cell neurokinin I receptor (NK-1R) to enhance IFN-gamma production. NK-1R on T cells is inducible. We studied mechanisms regulating T cell NK-1R expression. Murine splenocytes were cultured for 4 h with or without rIL-12 or rIL-18. Both IL-12 and IL-18 induced splenic T cells to express NK-1R transcripts. Induction was blocked by actinomycin D, but not cycloheximide, suggesting that protein synthesis was not required for initiation of NK-1R gene transcription. Inhibition of T cell NF-kappaB activation or NF-kappaB nuclear translocation also blocked NK-1R transcription. IL-12 and IL-18 strongly induce NK-IR mRNA expression in splenocytes from Stat4(-/-) mice, suggesting that the Stat4 pathway was not required for the induction of NK-1R transcription. Splenic T cells exposed to IL-12 or IL-18 in the presence of IL-10 expressed no NK-1R mRNA. However, TGFbeta did not prevent NK-1R mRNA expression. Thus, IL-12 and IL-18 induce T cells to express NK-1R through NF-kappaB activation. IL-10, a regulator of the Th1 response, blocks this activation. These data further suggest that SP and NK-1R, which promote IFN-gamma synthesis, are part of the Th1 pathway of immunity.