prostaglandin-d2 and Multiple-Sclerosis

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of proteins. The role of PPARs in regulating the transcription of genes involved in glucose and lipid metabolism has been extensively characterized. Interestingly, PPARs have also been demonstrated to mediate inflammatory responses. Microglia participate in pathology associated with multiple sclerosis (MS). Upon activation, microglia produce molecules including NO and TNF-alpha that can be toxic to CNS cells including myelin-producing oligodendrocytes and neurons, which are compromised in the course of MS. Previously, we and others demonstrated that PPAR-gamma agonists including 15d-PGJ(2) are effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. PPAR-gamma modulation of EAE may occur, at least in part, by inhibition of microglial cell activation. Here, we indicate that 15d-PGJ(2) is a more potent inhibitor of microglial activation than thiazolidinediones, which are currently used to treat diabetes. Furthermore, 15d-PGJ(2) acts cooperatively with 9-cis retinoic acid, the ligand for the retinoid X receptor (RXR), in inhibiting microglial cell activation. This suggests that 15d-PGJ(2) and 9-cis RA inhibit cell activation through the formation of PPAR-gamma/RXR heterodimers. Interestingly, PGA(2), which like 15d-PGJ(2) is a cyclopentenone prostaglandin, but which unlike 15d-PGJ(2) does not bind PPAR-gamma, is a potent inhibitor of microglial cell activation. Collectively, these studies suggest that 15d-PGJ(2) inhibits microglial cell activation by PPAR-gamma-dependent as well as PPAR-gamma-independent mechanisms. The studies further suggest that the PPAR-gamma agonist 15d-PGJ(2) in combination with retinoids may be effective in the treatment of MS.

Topics: Animals; Disease Models, Animal; Humans; Microglia; Models, Biological; Multiple Sclerosis; Neurons; PPAR gamma; Prostaglandin D2; Tretinoin

The 15-deoxi delta prostaglandin J(2) (15d-PGJ(2)) is a peroxisome proliferator-activated receptor-gamma agonist with potent anti-inflammatory properties. It has been suggested that 15d-PGJ(2) may modulate multiple sclerosis (MS).. Here, we investigated the plasma levels of 15d-PGJ(2) by enzyme-linked immunoassay in 28 healthy controls and 140 MS patients [30 patients with primary-progressive MS, 28 patients with secondary-progressive MS, and 82 patients with relapsing-remitting MS (28 patients during clinical remission, 25 patients during relapse, and 29 treated with interferon-beta - IFN-beta)].. Levels of 15d-PGJ(2) were similar between healthy controls and untreated MS patients with different clinical courses of the disease. Treatment with IFN-beta had no effect on levels of 15d-PGJ(2).. Although these findings suggest that 15d-PGJ(2) is not involved in the acute or chronic phases of the disease, further studies measuring 15d-PGJ(2) in cerebrospinal fluid samples are needed before excluding a role of 15d-PGJ(2) in MS.

Topics: Adult; Anti-Inflammatory Agents; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interferon-beta; Male; Middle Aged; Multiple Sclerosis; Prostaglandin D2

Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease model for multiple sclerosis (MS). We have shown earlier that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and curcumin ameliorate EAE by modulating inflammatory signaling pathways in T lymphocytes. Toll-like receptors (TLRs), expressed primarily in innate immune cells, play critical roles in the pathogenesis of EAE. T lymphocytes also express TLRs and function as costimulatory receptors to upregulate proliferation and cytokine production in response to specific agonists.. In this study, we show that naïve CD4(+) and CD8(+) T cells express detectable levels of TLR4 and TLR9 and that increase after the induction of EAE in SJL/J and C57BL/6 mice by immunization with PLPp139-151 and MOGp35-55 antigen, respectively. It is interesting to note that in vivo treatment with 15d-PGJ2 or curcumin results in a significant decrease in TLR4 and TLR9 expression in CD4(+) and CD8(+) T cells in association with the amelioration of EAE.. Although the exact mechanisms are not known, the modulation of TLR expression in T lymphocytes by 15d-PGJ(2) and curcumin suggests new therapeutic targets in the treatment of T cell-mediated autoimmune diseases.

Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Curcumin; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Freund's Adjuvant; Glycoproteins; Humans; Immunization; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Proteolipid Protein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Prostaglandin D2; Toll-Like Receptor 4; Toll-Like Receptor 9

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.

Topics: Animals; Astrocytes; Cells, Cultured; Chemokines; Enzyme-Linked Immunosorbent Assay; Mice; Microglia; Multiple Sclerosis; Nitric Oxide; Prostaglandin D2; Prostaglandins A

We analyzed CSF from patients with multiple sclerosis, patients with other neurologic diseases, and healthy controls for the presence of prostaglandin (PG) E2, F2 alpha, D2, I, A, and leukotriene (LT) C4. Control CSF had little measurable PGs or LTs. CSF eicosanoids from patients with progressive MS were increased. We found PGD2 only in MS CSF. CSF monocytes from patients in active disease produced significantly increased PGD, PGE, and LTC4 than paired peripheral blood monocytes and monocytes from healthy controls. We saw no significant difference in LTC4 production between MS and control peripheral blood monocytes.

Topics: Antigen-Presenting Cells; Cell Movement; Central Nervous System; Eicosanoids; Humans; Multiple Sclerosis; Nervous System Diseases; Prostaglandin D2; Prostaglandins; Reference Values; SRS-A