P38? and p38? kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation.

ABSTRACT: On the basis mainly of pharmacological experiments, the p38? MAP kinase isoform has been established as an important regulator of immune and inflammatory responses. However, the role of the related p38? and p38? kinases has remained unclear. Here, we show that deletion of p38? and p38? impaired the innate immune response to lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) ligand, by blocking the extracellular signal-regulated kinase 1/2 (ERK1/2) activation in macrophages and dendritic cells. p38? and p38? were necessary to maintain steady-state levels of tumor progression locus 2 (TPL2), the MKK kinase that mediates ERK1/2 activation after TLR4 stimulation. TNF?, IL-1?, and IL-10 production were reduced in LPS-stimulated macrophages from p38?/?-null mice, whereas IL-12 and IFN? production increased, in accordance with the known effects of TPL2/ERK1/2 signaling on the induction of these cytokines. Furthermore, p38?/?-deficient mice were less sensitive than controls to LPS-induced septic shock, showing lower TNF? and IL-1? levels after challenge. Together, our results establish p38? and p38? as key components in innate immune responses.

SUBMITTER: Risco A 

PROVIDER: S-EPMC3396476 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other