P38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation

TY - JOUR

T1 - P38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation

AU - Risco, Ana

AU - Del Dresno, Carlos

AU - Mambol, Agnes

AU - Alsina-Beauchamp, Dayanira

AU - MacKenzie, Kirsty F.

AU - Yang, Huei-Ting

AU - Barber, Domingo F.

AU - Morcelle, Carmen

AU - Arthur, J. Simon C.

AU - Ley, Steven C.

AU - Ardavin, Carlos F.

AU - Cuenda, Ana

N1 - Copyright 2012 Elsevier B.V., All rights reserved.

PY - 2012/7/10

Y1 - 2012/7/10

N2 - On the basis mainly of pharmacological experiments, the p38aMAP kinase isoform has been established as an important regulator of immune and inflammatory responses. However, the role of the related p38? and p38d kinases has remained unclear. Here, we show that deletion of p38? and p38d 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 p38d were necessary to maintain steady-state levels of tumor progression locus 2 (TPL2), the MKK kinase that mediates ERK1/2 activation after TLR4 stimulation. TNFa, IL-1ß, and IL-10 production were reduced in LPS-stimulated macrophages from p38?/d-null mice, whereas IL-12 and IFNß production increased, in accordance with the known effects of TPL2/ERK1/2 signaling on the induction of these cytokines. Furthermore, p38?/d-deficient mice were less sensitive than controls to LPS-induced septic shock, showing lower TNFa and IL-1ß levels after challenge. Together, our results establish p38? and p38d as key components in innate immune responses.

AB - On the basis mainly of pharmacological experiments, the p38aMAP kinase isoform has been established as an important regulator of immune and inflammatory responses. However, the role of the related p38? and p38d kinases has remained unclear. Here, we show that deletion of p38? and p38d 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 p38d were necessary to maintain steady-state levels of tumor progression locus 2 (TPL2), the MKK kinase that mediates ERK1/2 activation after TLR4 stimulation. TNFa, IL-1ß, and IL-10 production were reduced in LPS-stimulated macrophages from p38?/d-null mice, whereas IL-12 and IFNß production increased, in accordance with the known effects of TPL2/ERK1/2 signaling on the induction of these cytokines. Furthermore, p38?/d-deficient mice were less sensitive than controls to LPS-induced septic shock, showing lower TNFa and IL-1ß levels after challenge. Together, our results establish p38? and p38d as key components in innate immune responses.

UR - https://www.scopus.com/pages/publications/84863936555

U2 - 10.1073/pnas.1207290109

DO - 10.1073/pnas.1207290109

M3 - Article

C2 - 22733747

AN - SCOPUS:84863936555

SN - 0027-8424

VL - 109

SP - 11200

EP - 11205

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 28

ER -