P38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation. / Risco, Ana; Del Dresno, 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 F.; Cuenda, Ana.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 28, 10.07.2012, p. 11200-11205.Research output: Contribution to journal › Article
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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
A1 - Risco,Ana
A1 - Del Dresno,Carlos
A1 - Mambol,Agnes
A1 - Alsina-Beauchamp,Dayanira
A1 - MacKenzie,Kirsty F.
A1 - Yang,Huei-Ting
A1 - Barber,Domingo F.
A1 - Morcelle,Carmen
A1 - Arthur,J. Simon C.
A1 - Ley,Steven C.
A1 - Ardavin,Carlos F.
A1 - Cuenda,Ana
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
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.
U2 - 10.1073/pnas.1207290109
DO - 10.1073/pnas.1207290109
M1 - Article
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
SN - 0027-8424
IS - 28
VL - 109
SP - 11200
EP - 11205
ER -