title: The early synthesis of p35 and activation of CDK5 in LPS-stimulated macrophages suppresses interleukin-10 production.
abstract: Interleukin-10 (IL-10) is an important anti-inflammatory cytokine that is produced primarily by macrophages. We investigated mechanisms by which the timing of IL-10 production was controlled in macrophages and found that cyclin-dependent kinase 5 (CDK5) activity was markedly increased in lipopolysaccharide (LPS)-stimulated macrophages through the synthesis of the CDK5-binding partner and activator p35. Degradation of p35 released the inhibition on anti-inflammatory signaling mediated by CDK5-p35 complexes. The transiently active CDK5-p35 complexes limited the LPS-stimulated phosphorylation and activation of various mitogen-activated protein kinases (MAPKs), thereby preventing the premature production of SOCS3 (suppressor of cytokine signaling 3), an inhibitor of inflammatory responses in macrophages, and IL-10. Furthermore, we showed that dextran sodium sulfate failed to induce colitis in p35-deficient mice, which was associated with the enhanced production of IL-10 by macrophages. Together, our results suggest that CDK5 enhances the inflammatory function of macrophages by inhibiting the MAPK-dependent production of IL-10.
authors.affiliation: Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, South Korea.
authors.forename: Yi Rang
authors.initials: YR
authors.lastname: Na
authors.affiliation: Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, South Korea.
authors.forename: Daun
authors.initials: D
authors.lastname: Jung
authors.affiliation: Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, South Korea.
authors.forename: Gyo Jeong
authors.initials: GJ
authors.lastname: Gu
authors.affiliation: Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, South Korea.
authors.forename: Ah Ram
authors.initials: AR
authors.lastname: Jang
authors.affiliation: Korea Brain Research Institute, 61 Chumdan-ro, Dong-gu, Daegu 701-300, South Korea.
authors.forename: Yoo-Hun
authors.initials: YH
authors.lastname: Suh
authors.affiliation: Department of Microbiology and Immunology, and Institute of Endemic Disease, Seoul National University College of Medicine, 103 Daehak-ro, Chongno-gu, Seoul 110-799, South Korea. lamseok@snu.ac.kr.
authors.forename: Seung Hyeok
authors.initials: SH
authors.lastname: Seok
mesh_terms: D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C492236:Cdk5r1 protein, mouse; C556062:IL10 protein, mouse; D008070:Lipopolysaccharides; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016753:Interleukin-10; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases