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

Ana Risco, Carlos Del Dresno, Agnes Mambol, Dayanira Alsina-Beauchamp, Kirsty F. MacKenzie, Huei-Ting Yang, Domingo F. Barber, Carmen Morcelle, J. Simon C. Arthur, Steven C. Ley, Carlos F. Ardavin, Ana Cuenda

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    Abstract

    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.
    Original languageEnglish
    Pages (from-to)11200-11205
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume109
    Issue number28
    DOIs
    Publication statusPublished - 10 Jul 2012

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    Risco, A., Del Dresno, C., Mambol, A., Alsina-Beauchamp, D., MacKenzie, K. F., Yang, H-T., Barber, D. F., Morcelle, C., Arthur, J. S. C., Ley, S. C., Ardavin, C. F., & Cuenda, A. (2012). P38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation. Proceedings of the National Academy of Sciences of the United States of America, 109(28), 11200-11205. https://doi.org/10.1073/pnas.1207290109