The neuropeptide substance P activates p38 mitogen-activated protein kinase resulting in IL-6 expression independently from NF-kappa B

Substance P (SP), a member of the tachykinin peptide family, is a major med iator of neuroimmunomodulatory activities and neurogenic inflammation withi n the central and peripheral nervous system. SP has been shown to induce th e expression of proinflammatory cytokines such as IL-6, which might be impl icated in the etiopathology of several human brain disorders, We showed in a previous study that nanomolar concentrations of SP triggered activation o f NF-kappaB, a transcription factor involved in the control of cytokine exp ression. However, activation of NF-kappaB was not involved in SP-induced ex pression of IL-6, Here, we describe p38 mitogen-activated protein kinase (p 38 MAP kappa) as a signal transduction component that operates Independentl y from NF-kappaB activation and that mediates SP-induced IL-6 expression in the human astrocytoma cell line U373 R-IG. SP induced the phosphorylation of p38 MAP kappa within 10 min, and this activation persisted up to 30 min and was independent from p24/44 MAP kappas and protein kinase C activation, which all are induced after stimulation with SP, As shown by EMSA, p38 MAP kappa was not involved in SP-induced activation of NF-kappaB, p38 MAP kapp a, however, mediated SP-induced IL-6 expression as shown by the use of spec ific inhibitors of this kinase. Our results suggest that activation of p38 MAP kappa is an important component controlling neurogenic inflammation wit hin the CNS independently from NF-kappaB, Drugs targeting this MAP kappa ma y therefore interfere with SP-correlated neuropsychiatric disorders and may represent a therapeutic approach in these disorders.