Blockade of cytosolic phospholipase A2 alpha prevents experimental autoimmune encephalomyelitis and diminishes development of Th1 and Th17 responses.
Cytosolic phospholipase A2 alpha (cPLA2 alpha) is the rate-limiting enzyme for release of arachidonic acid, which is converted primarily to prostaglandins via the cyclooxygenase (COX) 1/2 pathways, and leukotrienes via the 5-lipoxygenase (LO) pathway. We utilized inhibitors of cPLA2 alpha, COX-1/2 and 5-LO to determine the potential roles of these enzymes in development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Blocking cPLA2 alpha prevented EAE development and greatly reduced antigen-induced production of Th1-type cytokines and IL-17. Blocking COX-1/2 delayed onset and reduced severity of EAE, and reduced production of Th1-type cytokines, but not IL-17. Blocking 5-LO delayed onset and reduced cumulative severity of EAE, but did not reduce production of Th1-type cytokines or IL-17. Finally, blockade of cPLA2 alpha from the onset of clinical EAE reduced duration of EAE relapses. Therefore, cPLA2 alpha represents a potential therapeutic target for treatment of MS.
Marusic
Suzana
S
Hooke Laboratories Inc., Lawrence, MA 01843, United States. marusic@hookelabs.com
Thakker
Paresh
P
Pelker
Jeffrey W
JW
Stedman
Nancy L
NL
Lee
Katherine L
KL
McKew
John C
JC
Han
Lixin
L
Xu
Xin
X
Wolf
Stan F
SF
Borey
Adam J
AJ
Cui
Junqing
J
Shen
Marina W H
MW
Donahue
Fran
F
Hassan-Zahraee
Mina
M
Leach
Michael W
MW
Shimizu
Takao
T
Clark
James D
JD
D000704:Analysis of Variance; D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology* / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006023:Glycoproteins; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors*; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D063308:Myelin-Oligodendrocyte Glycoprotein; D009288:Naproxen / Q000494:pharmacology / Q000627:therapeutic use; D010446:Peptide Fragments; D012720:Severity of Illness Index; D055906:Seveso Accidental Release; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D018417:Th1 Cells / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
C531069:4-(3-(5-chloro-2-(2-(((2,6-dimethylbenzyl)sulfonyl)amino)ethyl)-1-(diphenylmethyl)-1H-indol-3-yl)propyl)benzoic acid; D001565:Benzoates; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D016859:Lipoxygenase Inhibitors; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D013449:Sulfonamides; C445081:myelin oligodendrocyte glycoprotein (35-55); D009288:Naproxen; D054513:Group IV Phospholipases A2; C063449:zileuton; D006918:Hydroxyurea