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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-07, Vol.109 (28), p.11200-11205
• Main Authors: Risco, Ana, del Fresno, Carlos, Mambol, Agnes, Alsina-Beauchamp, Dayanira, MacKenzie, Kirsty F, Yang, Huei-Ting, Barber, Domingo F, Morcelle, Carmen, Arthur, J. Simon C, Ley, Steven C, Ardavin, Carlos, Cuenda, Ana
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Cattle; Cell lines; Cells, Cultured; Cellular immunity; Culture Media, Conditioned - pharmacology; Cytokines; Cytokines - metabolism; Dendritic cells; Gene Deletion; Gene Expression Regulation; Humans; Immunity, Innate; inflammation; innate immunity; interleukin-10; interleukin-12; interleukin-1beta; lipopolysaccharides; loci; Macrophages; Macrophages - metabolism; MAP Kinase Signaling System; Messenger RNA; Mice; mitogen-activated protein kinase; Mitogen-Activated Protein Kinase 13 - chemistry; Mitogen-Activated Protein Kinase 3 - metabolism; p38 Mitogen-Activated Protein Kinases - chemistry; Phosphorylation; Physiological regulation; Protein Isoforms; Septic shock; Shock, Septic - metabolism; Toll-like receptor 4; Toll-Like Receptor 4 - metabolism; tumor necrosis factor-alpha
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1207290109

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.