p38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation

On the basis mainly of pharmacological experiments, the p38 alpha MAP kinase isoform has been established as an important regulator of immune and inflammatory responses. However, the role of the related p38 gamma and p38 delta kinases has remained unclear. Here, we show that deletion of p38 gamma and p38 delta 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 gamma and p38 delta 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 alpha, IL-1 beta, and IL-10 production were reduced in LPS-stimulated macrophages from p38 gamma/delta-null mice, whereas IL-12 and IFN beta production increased, in accordance with the known effects of TPL2/ERK1/2 signaling on the induction of these cytokines. Furthermore, p38 gamma/delta-deficient mice were less sensitive than controls to LPS-induced septic shock, showing lower TNF alpha and IL-1 beta levels after challenge. Together, our results establish p38 gamma and p38 delta as key components in innate immune responses.