ERK5 Activation Inhibits Inflammatory Responses via Peroxisome Proliferator-activated Receptor δ (PPARδ) Stimulation

Abstract

Peroxisome proliferator-activated receptors (PPAR) decrease the production of cytokine and inducible nitric-oxide synthase (iNOS) expression, which are associated with aging-related inflammation and insulin resistance. Recently, the involvement of the induction of heme oxygenase-1 (HO-1) in regulating inflammation has been suggested, but the exact mechanisms for reducing inflammation by HO-1 remains unclear. We found that overexpression of HO-1 and [Ru(CO) 3 Cl 2 ] 2 , a carbon monoxide (CO)-releasing compound, increased not only ERK5 kinase activity, but also its transcriptional activity measured by luciferase assay with the transfection of the Gal4-ERK5 reporter gene. This transcriptional activity is required for coactivation of PPAR␦ by ERK5 in C2C12 cells. [Ru(CO) 3 Cl 2 ] 2 activated PPAR␦ transcriptional activity via the MEK5/ERK5 signaling pathway. The inhibition of NF-B activity by ERK5 activation was reversed by a dominant negative form of PPAR␦ suggesting that ERK5/PPAR␦ activation is required for the anti-inflammatory effects of CO and HO-1. Based on these data, we propose a new mechanism by which CO and HO-1 mediate anti-inflammatory effects via activating ERK5/PPAR␦, and ERK5 mediates CO and HO-1-induced PPAR␦ activation via its interaction with PPAR␦.Muscle wasting is a major feature of the cachexia associated with diverse pathologies such as cancer, sepsis, diabetes, and aging (1). Several cytokines have been implicated in the pathogenesis of muscle wasting, most notably TNF-␣, 2 a pro-inflammatory cytokine that was originally called "cachectin" (1). In addition, aging-related chronic low grade inflammation by TNF-␣ plays an important role in insulin resistance (2). It has been proposed that chronic inflammation by TNF-␣-mediated NF-B activation and subsequent inducible nitric-oxide synthase (iNOS) induction relates to muscle wasting and insulin resistance as we will explain below. Cai et al. (3) have shown that activation of NF-B, through muscle-specific transgenic expression of activated IB kinase ␤ (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-B through expression of IB suppressor (MISR), and denervation and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-B inhibition in MISR mice, which is consistent with a critical role for NF-B in the pathology of muscle wasting, especially in diabetes and during the process of aging (3). Recent studies suggest the involvement of iNOS in the pathogenesis of insulin resistance (4, 5). First, most inducers of insulin resistance, including obesity (6), free fatty acids (7), hyperglycemia (8, 9), TNF-␣, oxidative stress, and endotoxin, increase iNOS expression. Second, iNOS mediates the impaired insulin-stimulated glucose uptake by treatment with TNF-␣ and lipopolysaccharide in cultured muscle cells (10). iNOS expression is elevated in skeletal muscle of patients with type 2 diabetes (11, 12), and high fat diet-induced...

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands inhibit growth of UACC903 and MCF7 human cancer cell lines

“…Anti-inflammatory activity of PPARβ/δ and/or PPARβ/δ ligands has been shown in a number of different models including immune cells, colon epithelium, macrophages, cardiomyocytes, keratinocytes, myoblasts, endothelial cells, nerve tissue and hepatocytes Graham et al 2005;Hollingshead et al 2007b;Jakobsen et al 2006;Kim et al 2006;Nagasawa et al 2006;Peters et al 2000;Polak et al 2005;Rival et al 2002;Schmuth et al 2004;Welch et al 2003;Woo et al 2006). There is also strong evidence that ligand activation of PPARβ/δ promotes terminal differentiation in intestinal epithelium, breast and colon cancer cell lines, trophoblasts and primary keratinocytes (Aung et al 2006;Burdick et al 2007;Kim et al 2006;Marin et al 2006;Nadra et al 2006;Schmuth et al 2004;Tan et al 2001;Varnat et al 2006;Westergaard et al 2001).…”

Mitogen activated protein kinases: a role in inflammatory bowel disease?

“…Along with ERK1/2, ERK5 is also considered as a classical MAPK [11,20]. However, unlike ERK1/2, its association to IBD (if any) has not been detailed, although reports have indicated a role for this protein in potentiating antiinflammatory signals and promoting macrophage survival and proliferation [21,22]. The atypical ERK MAPKs remain elusive in revealing their physiological roles.…”

Ligand activation of peroxisome proliferator-activated receptor-β/δ(PPARβ/δ) inhibits cell growth of human N/TERT-1 keratinocytes

“…Indeed, there is strong evidence that ligand activation of PPARβ/δ induces terminal differentiation of keratinocytes [24][25][26][27] and it has also been shown that differentiation of breast and colon cancer cell lines is associated with increased expression of PPARβ/δ [28]. Additionally, PPARβ/δ ligands can significantly inhibit the expression of proinflammatory molecules such as interleukins and TNFα in immune cells [29,30], cardiomyocytes [31], a human endothelial cell line [32], C2C12 mouse myoblasts [33] and liver [34]. Thus, while there is great potential for PPARβ/δ ligands as therapeutic agents, this potential is negatively affected by the controversy regarding the biological role(s) of PPARβ/δ in cell proliferation and carcinogenesis.…”