Cyclopentenone prostaglandins PGA2 and 15-deoxy-?12,14 PGJ2 suppress activation of murine microglia and astrocytes: Implications for multiple sclerosis

Abstract

The cyclopentenone prostaglandin (cPG) 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) has been identified as a potent antiinflammatory agent that is able to inhibit the activation of macrophages and microglia. Additionally, 15d-PGJ(2) is able to ameliorate the clinical manifestations of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Many biological effects of 15d-PGJ(2) have been attributed to the peroxisome proliferator activated receptor-gamma (PPAR-gamma). PGA(2), like 15d-PGJ(2), is a cPG. The aim of this study is to compare the relative effectiveness of these two cPGs in inhibiting the inflammatory response of mouse microglia and astrocytes, two cell types that upon activation may contribute to the pathology of EAE and MS. Purified primary mouse microglia and astrocytes were treated with either 15d-PGJ(2) or PGA(2) and then stimulated with either lipopolysaccharide (LPS) or a combination of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha. The results show that 15d-PGJ(2) and PGA(2) both potently inhibited the production of nitrite, as well as proinflammatory cytokines and chemokines, from microglia and astrocytes. Generally, regulation of NO production was more sensitive to 15d-PGJ(2), however, cytokine and chemokine production was more sensitive to PGA(2) treatment. These results demonstrate for the first time that PGA(2) is a potent antiinflammatory mediator.

Peroxisome Proliferator-Activated Receptor-γ Agonists Suppress the Production of IL-12 Family Cytokines by Activated Glia

“…Chronically activated microglia and astrocytes produce proinflammatory molecules that may contribute to the loss of neurons and oligodendrocytes, cells that are compromised in MS. Previously, we demonstrated that PPAR-␥ agonists block the production of proinflammatory molecules by CNS glia (23)(24)(25). Collectively, these studies suggest that PPAR-␥ agonists may modulate the development of EAE in part through effects on glial cell activation.…”

“…We have also demonstrated that these agonists potently suppress the production of proinflammatory mediators, including NO, various cytokines, and chemokines by primary mouse microglia and astrocytes (23)(24)(25). These studies suggest that PPAR-␥ agonists may modulate EAE in part through effects on resident CNS glia.…”

Liver X receptor and retinoid X receptor agonists inhibit inflammatory responses of microglia and astrocytes

“…Previously, we and others have demonstrated that PPARs also are important modulators of inflammation (Kielian and Drew, 2003b;Ricote et al, 1998). For example, PPAR-γ agonists including the naturally occurring prostaglandin metabolite 15d-PGJ2 and synthetic ligands including thiazolidinediones which are used commonly for the treatment of type II diabetes, suppressed immune function of cells including macrophages T cells, and CNS glia (Clark et al, 2000;Drew and Chavis, 2001a;Jiang et al, 1998;Ricote et al, 1998;Storer et al, 2005a;Storer et al, 2005b). PPAR-γ ligands also suppress inflammation and pathology in animal models of atherosclerosis, arthritis, inflammatory bowel disease and MS (Diab et al, 2002;Feinstein et al, 2002;Kawahito et al, 2000;Li et al, 2000;Natarajan and Bright, 2002;Niino et al, 2001;Su et al, 1999).…”

Pioglitazone rapidly reduces neuropathic pain through astrocyte and nongenomic PPARγ mechanisms

“…TZDs agonize PPARγ expressed in spinal cord [58] and brain [17] astrocytes to reduce activation [6] and GFAP upregulation [34]. Dosing over several weeks produced anti-hyperalgesia that was associated with reductions in spinal GFAP [39;53;60], injury-induced pro-inflammatory cytokine expression [40], and in vitro astrocyte TNFα release [31;82]. A single injection of PPARγ agonist reduces neuropathic pain [13]; however, an important gap is whether there are acute effects on spinal astrocytes.…”