IL-18 and IL-12 Signal Through the NF-κB Pathway to Induce NK-1R Expression on T Cells

Abstract

Substance P engages the T cell neurokinin 1 receptor (NK-1R) to enhance IFN-γ 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-κB activation or NF-κB nuclear translocation also blocked NK-1R transcription. IL-12 and IL-18 strongly induce NK-1R 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, TGFβ did not prevent NK-1R mRNA expression. Thus, IL-12 and IL-18 induce T cells to express NK-1R through NF-κB activation. IL-10, a regulator of the Th1 response, blocks this activation. These data further suggest that SP and NK-1R, which promote IFN-γ synthesis, are part of the Th1 pathway of immunity.