p38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation
- 25 June 2012
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 109 (28), 11200-11205
- https://doi.org/10.1073/pnas.1207290109
Abstract
On the basis mainly of pharmacological experiments, the p38α MAP kinase isoform has been established as an important regulator of immune and inflammatory responses. However, the role of the related p38γ and p38δ kinases has remained unclear. Here, we show that deletion of p38γ and p38δ 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. p38γ and p38δ were necessary to maintain steady-state levels of tumor progression locus 2 (TPL2), the MKK kinase that mediates ERK1/2 activation after TLR4 stimulation. TNFα, IL-1β, and IL-10 production were reduced in LPS-stimulated macrophages from p38γ/δ-null mice, whereas IL-12 and IFNβ production increased, in accordance with the known effects of TPL2/ERK1/2 signaling on the induction of these cytokines. Furthermore, p38γ/δ-deficient mice were less sensitive than controls to LPS-induced septic shock, showing lower TNFα and IL-1β levels after challenge. Together, our results establish p38γ and p38δ as key components in innate immune responses.Keywords
This publication has 43 references indexed in Scilit:
- Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinaseCell Research, 2010
- Distinct Effects of p38α Deletion in Myeloid Lineage and Gut Epithelia in Mouse Models of Inflammatory Bowel DiseaseGastroenterology, 2010
- p38-γ–dependent gene silencing restricts entry into the myogenic differentiation programThe Journal of cell biology, 2009
- Tumor Progression Locus 2 (Map3k8) Is Critical for Host Defense againstListeria monocytogenesand IL-1β ProductionThe Journal of Immunology, 2009
- TPL-2 negatively regulates interferon-β production in macrophages and myeloid dendritic cellsThe Journal of Experimental Medicine, 2009
- Regulation of PKD by the MAPK p38δ in Insulin Secretion and Glucose HomeostasisCell, 2009
- The kinase p38α serves cell type–specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expressionNature Immunology, 2008
- The RAF proteins take centre stageNature Reviews Molecular Cell Biology, 2004
- Toll-like receptor signallingNature Reviews Immunology, 2004
- NF-κB1/p105 Regulates Lipopolysaccharide-Stimulated MAP Kinase Signaling by Governing the Stability and Function of the Tpl2 KinaseMolecular Cell, 2003