11 APRIL 2013 I VOLUME 121, NUMBER 15 causing local vasodilatation and by attracting and activating neutrophils, eosinophils, mast cells, monocytes, and macrophages. 5 DCs are known to express NK1R regardless of their maturation status, and SP has been reported to sustain the survival of DCs in culture and in living animals. 6 On the other hand, immunologic impacts of NK1R agonists on DCs remain relatively unknown. Using natural SP, homokinin-1, and a synthetic NK1R-specific SP homolog, Janelsins et al1 sought to fill in this gap. These investigators found that NK1R agonists increase surface expression of major histocompatibility complex (MHC) class II molecule, costimulatory molecules (CD40, CD80, and CD86), adhesion molecules (CD11b, CD18, and CD54), and CC chemokine receptor type 7 (CCR7) in murine bone marrow–derived DCs. Although NK1R agonists failed to alter the secretion of IL-1, IL-6, TNFa, and IL-12 by DCs, they potently inhibited IL-10 production. When injected subcutaneously after antigen loading, those DCs stimulated with NK1R agonists migrated efficiently to skin-draining LNs and elicited robust activation of CD4 and CD8 T cells producing interferon-g and antigen-specific cytotoxic T cells. How can those DCs that secrete only negligible amounts of IL-12 initiate type 1 immunity? The DCs pretreated with NK1R agonists were found to induce marked recruitment of Ly6C+ inflammatory DCs to the skin-draining LNs, where they physically interacted with inflammatory DCs and promoted their production of IL-12. Janelsins et al1 elegantly determined the source of IL-12 by transferring SP-pretreated DCs from IL-12 p35-deficient mice into wild-type recipient mice—these recipient mice still exhibited robust Th1-polarized immunity. Their findings demonstrate that NK1R agonists counteract with anti-inflammatory neuropeptides by directing DC functionality into contrary directions (see figure). At the same time, the above findings raise several important questions. What are the underlying mechanisms by which antiinflammatory neutropeptides and proinflammatory neuropeptides produce opposing outcomes in DCs? VIP, a-MSH, and CGRP are known to downregulate the transcription of inflammatory cytokine genes by activating the cyclic AMP (cAMP)–protein kinase A pathway, thereby inhibiting the nuclear factor-kB (NFkB) pathway. 2