Inhibition of p38/Mk2 signaling pathway improves the anti-inflammatory effect of WIN55 on mouse experimental colitis

Lab Invest. 2013 Mar;93(3):322-33. doi: 10.1038/labinvest.2012.177. Epub 2013 Feb 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Benzoxazines / pharmacology*
  • Chemokine CCL2 / blood
  • Chemokine CXCL1 / blood
  • Colitis / chemically induced
  • Colitis / drug therapy*
  • Colitis / pathology
  • DNA Primers / genetics
  • Dextran Sulfate / toxicity
  • Enzyme-Linked Immunosorbent Assay
  • Immunohistochemistry
  • Interleukin-6 / blood
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Morpholines / pharmacology*
  • Naphthalenes / pharmacology*
  • Peroxidase / metabolism
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Real-Time Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / blood


  • Anti-Inflammatory Agents
  • Benzoxazines
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Chemokine CXCL1
  • DNA Primers
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • Morpholines
  • Naphthalenes
  • Tumor Necrosis Factor-alpha
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Dextran Sulfate
  • Peroxidase
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases