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 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.
Department of Immunology and Oncology,  Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas (CNB/CSIC), 28049-Madrid,  Spain.
Ana
A
Risco
Carlos
C
del Fresno
Agnes
A
Mambol
Dayanira
D
Alsina-Beauchamp
Kirsty F
KF
MacKenzie
Huei-Ting
HT
Yang
Domingo F
DF
Barber
Carmen
C
Morcelle
J Simon C
JS
Arthur
Steven C
SC
Ley
Carlos
C
Ardavin
Ana
A
Cuenda
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D048292:Mitogen-Activated Protein Kinase 13 / Q000737:chemistry*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020033:Protein Isoforms; D012772:Shock, Septic / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000737:chemistry*
D017077:Culture Media, Conditioned; D016207:Cytokines; D020033:Protein Isoforms; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D048292:Mitogen-Activated Protein Kinase 13; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases