Macrophage deletion of p38alpha partially impairs lipopolysaccharide-induced cellular activation.
The activation of p38alpha, a MAPK family member, is associated with macrophage activation by microbial pattern molecules, such as LPS. The requirement of p38alpha in inflammatory responses has been shown in a number of studies using chemical inhibitors, though the inhibitors also inhibit p38beta and perhaps some other enzymes. In this study, we used conditional knockout of p38alpha in macrophages to address the role of p38alpha in macrophage activation. We found that p38alpha deficiency causes a significant inhibition in the production of LPS-induced TNF-alpha, IL-12, and IL-18, but it has little or no effect on IL-6 or IFN-beta production. Knockout of p38alpha in macrophages did not affect LPS-induced activation of the other major signaling pathways (NF-kappaB, Jnk, and Erk), nor did it affect the transcriptional activity of NF-kappaB. It had little inhibitory effect on LPS-induced AP-1 activity, but it significantly inhibited LPS-induced C/EBP-beta and CREB activation, indicating that the role of p38alpha in cytokine production in macrophages is at least in part through its regulation of C/EBP-beta and CREB activation. In addition, we also confirmed that p38alpha is important for phagocytosis of bacteria by macrophages. Our in vivo studies with two murine models showed that p38alpha is involved in sepsis. Collectively, our data demonstrate that p38alpha is an important player in inflammatory responses.
Kang
Young Jun
YJ
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Chen
Jianming
J
Otsuka
Motoyuki
M
Mols
Johann
J
Ren
Shuxun
S
Wang
Yinbin
Y
Han
Jiahuai
J
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004926:Escherichia coli / Q000502:physiology; D017353:Gene Deletion; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010586:Phagocytes / Q000201:enzymology; D015398:Signal Transduction / Q000187:drug effects; D013211:Staphylococcus aureus / Q000502:physiology; D015533:Transcriptional Activation / Q000235:genetics; D048069:Tumor Necrosis Factors / Q000378:metabolism
D016207:Cytokines; D008070:Lipopolysaccharides; D048069:Tumor Necrosis Factors; D048308:Mitogen-Activated Protein Kinase 14