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Macrophage Deletion of p38 Partially Impairs Lipopolysaccharide-Induced Cellular Activation¹

Young Jun Kang^2,*, Jianming Chen^2,*, Motoyuki Otsuka^*, Johann Mols^*, Shuxun Ren, Yinbin Wang and Jiahuai Han^3,*

^* Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037 and Molecular Biology Institute and the Departments of Anesthesiology and Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095

The activation of p38, a MAPK family member, is associated with macrophage activation by microbial pattern molecules, such as LPS. The requirement of p38 in inflammatory responses has been shown in a number of studies using chemical inhibitors, though the inhibitors also inhibit p38β and perhaps some other enzymes. In this study, we used conditional knockout of p38 in macrophages to address the role of p38 in macrophage activation. We found that p38 deficiency causes a significant inhibition in the production of LPS-induced TNF-, IL-12, and IL-18, but it has little or no effect on IL-6 or IFN-β production. Knockout of p38 in macrophages did not affect LPS-induced activation of the other major signaling pathways (NF-B, Jnk, and Erk), nor did it affect the transcriptional activity of NF-B. It had little inhibitory effect on LPS-induced AP-1 activity, but it significantly inhibited LPS-induced C/EBP-β and CREB activation, indicating that the role of p38 in cytokine production in macrophages is at least in part through its regulation of C/EBP-β and CREB activation. In addition, we also confirmed that p38 is important for phagocytosis of bacteria by macrophages. Our in vivo studies with two murine models showed that p38 is involved in sepsis. Collectively, our data demonstrate that p38 is an important player in inflammatory responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants AI41637, AI54696 (to J.H.), and HL62311 and HL080111 (to Y.W.) from the National Institutes of Health.

² Y.J.K. and J.C. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Jiahuai Han, Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037. E-mail address: jhan{at}scripps.edu

⁴ Abbreviations used in this paper: RNA Pol II, RNA polymerase II; MK2, MAPK-activated protein kinase 2; ChIP, chromatin immunoprecipitation; CLP, cecal ligation and puncture.