title: Inhibition of p38/Mk2 signaling pathway improves the anti-inflammatory effect of WIN55 on mouse experimental colitis.
abstract: P38/Mk2 (mitogen-activated protein kinase (MAPK)-activated protein kinase-2, also known as MAKAP kinase-2) is a member of the mitogen-activated protein kinases (MAPKs) family, and participates in inflammatory responses directly or indirectly. WIN55, 212-2 (WIN55) is a synthetic non-selective agonist of cannabinoid (CB) receptors with remarkable anti-inflammatory properties. This study was to explore the roles of WIN55 and p38/Mk2 signaling pathway in dextran sodium sulfate (DSS)-induced mouse colitis and ascertain their anti-inflammatory mechanisms. Colitis was induced in C57BL Mk2 gene homozygous deletion (Mk2-/-) and wild-type mice by replacing the drinking water with 4% DSS solution for 7 days. DSS-treated mice developed bloody stool, weight loss, and eye-visible multiple bleeding ulcers on colon mucosa. The mRNA expressions levels of TNF-α and IL-6, as well as the protein levels of p38 and its phosphorylated form (p-p38), were upregulated in the colon. The plasma levels of TNF-α, IL-6, cytokine-induced neutrophil chemoattractant-1 (CINC-1), monocyte chemoattractant protein-1 (MCP-1), and lung myeloperoxidase (MPO) activities were raised; however, all these changes were less severe in Mk2-/- mice. After WIN55 intervention, the Mk2-/- mice recovered faster and better from the induced colitis than their wild-type counterparts. The results indicate that the Mk2 homozygous deletion in mice impedes the induction of experimental colitis by DSS, confirming the notion that p38/Mk2 is involved in this inflammatory response. WIN55 protects mice against DSS-induced colitis, in particular when the p38/Mk2 pathway is obstructed, implying that the activation of CB system, together with blocking of p38/Mk2 pathway, serves as a potential drug target for colitis treatment.
authors: Department of Pathophysiology, Institute of Digestive Disease, Tongji University School of Medicine, Shanghai, China. liyongyu@tongji.edu.cn
authors: Yu Y
authors: YY
authors: Li
authors: Birol
authors: B
authors: Yuece
authors: Hua M
authors: HM
authors: Cao
authors: Hong X
authors: HX
authors: Lin
authors: Shuai
authors: S
authors: Lv
authors: Jie C
authors: JC
authors: Chen
authors: Stephanie
authors: S
authors: Ochs
authors: Andrej
authors: A
authors: Sibaev
authors: Elisabeth
authors: E
authors: Deindl
authors: Claus
authors: C
authors: Schaefer
authors: Martin
authors: M
authors: Storr
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000097:blood; D054360:Chemokine CXCL1 / Q000097:blood; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D016264:Dextran Sulfate / Q000633:toxicity; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000893:Anti-Inflammatory Agents; D048588:Benzoxazines; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D017931:DNA Primers; D016264:Dextran Sulfate; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D009281:Naphthalenes; D009195:Peroxidase; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2; C491768:Ccl2 protein, mouse; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone