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 antiinflammatory 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 À / À ) 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-a 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-a, 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 À / À mice. After WIN55 intervention, the Mk2 À / À 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.

The cannabinoid‐1 receptor inverse agonist taranabant reduces abdominal pain and increases intestinal transit in mice

“…Importantly, the analgesic action induced by taranabant was mediated by CB1 receptors, as it was abolished in CB1 −/− mice. This observation reveals a similar mode of action for both CB1 agonists and inverse agonists and points out the importance of CB1 receptors as a therapeutic aim for future drugs targeting IBS‐C.…”

Alterations in biomechanical properties and microstructure of colon wall in early-stage experimental colitis

“…no. 160110; MP Biomedicals, Solon, OH, USA) for 7 days continuously, as described by Li et al (20). At 7 days after the induction of colitis, stool consistency and the presence of occult blood was examined and documented daily.…”

“…The MS was the sum of the three scores, ranging between 0 (healthy) and 12 (maximal). Scoring was conducted as reported previously by Li et al (20) and Kimball et al (21). …”

The Endocannabinoid/Endovanilloid N-Arachidonoyl Dopamine (NADA) and Synthetic Cannabinoid WIN55,212-2 Abate the Inflammatory Activation of Human Endothelial Cells

“…Using a panel of synthetic cannabinoids, phytocannabinoids, and eCBs, we found that the synthetic cannabinoid WIN55,212-2 and the eCB NADA have the ability to dampen the activation of primary human lung microvascular ECs (HMVEC-lung) by a variety of inflammatory agonists, including bacterial lipopeptides (TLR2 agonist), lipopolysaccharide (LPS) (TLR4 agonist), and TNF␣. Although the anti-inflammatory properties of WIN55,212-2 have previously been described, only a few reports have described the physiological functions of NADA, including its role in inflammation (16,(25)(26)(27)(28)(29)(30)(31)(32).…”