Myristoylated alanine-rich C kinase substrate (MARCKS) regulates the expression of proinflammatory cytokines in macrophages through activation of p38/JNK MAPK and NF-κB.
MARCKS, a substrate of protein kinase C, is involved in various processes associated with cytoskeletal movement. Although the expression of MARCKS is highly induced in macrophages, its role in macrophage function has not been studied in detail. Notably, the suppression of MARCKS expression in macrophage cell lines blocked LPS-induced expression of TNF-α at the transcriptional level. Treatment of macrophages with MARCKS N-terminus sequence (MANS) and effector domain (ED) peptides, which mimic functional domains and block the phosphorylation of MARCKS, suppressed the LPS-induced expression of TNF-α through suppression of p38 and JNK MAPKs and NF-κB. Treatment of mice with MANS peptide reduced serum TNF-α and IL-6 levels and resulted in 40% survival of mice after the administration of a lethal dose of LPS. These data demonstrate that MARCKS is involved in the regulation of proinflammatory cytokine expression in macrophages and that MARCKS-derived peptides can be used to suppress inflammatory responses.
School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Republic of Korea.
Sang-Min
SM
Lee
Department of Pharmacology, Brain Science & Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu 700-422, Republic of Korea.
Kyoungho
K
Suk
School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Republic of Korea. Electronic address: whl@knu.ac.kr.
Won-Ha
WH
Lee
D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000235:genetics* / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D051379:Mice; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D016328:NF-kappa B / Q000235:genetics* / Q000276:immunology; D010455:Peptides / Q000494:pharmacology*; D061251:Primary Cell Culture; D011493:Protein Kinase C / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D018805:Sepsis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D015398:Signal Transduction; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000276:immunology; D000093242:Interleukin-6 Inhibitors
D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D048670:MAP Kinase Kinase 4; D008565:Membrane Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D016328:NF-kappa B; D010455:Peptides; D011493:Protein Kinase C; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C000619710:MARCKS protein, human; C000619711:Marcks protein, mouse
Cytokine; LPS; MARCKS; Macrophages; Signaling