Protective role for cytosolic phospholipase A₂α in autoimmune diabetes of mice

Abstract

Cytosolic phospholipase A 2 a (cPLA 2 a) plays an important role in arachidonate pathway. To investigate the contribution of cPLA 2 a to autoimmune diabetes, we established non-obese diabetic (NOD) mouse, an excellent model for human type 1 diabetes, deficient in cPLA 2 a. These mice showed severe insulitis and a higher incidence of diabetes. In their macrophages, decreased prostaglandin E 2 (PGE 2 ) induced by cPLA 2 a deficiency, and the increase in production of tumor necrosis factor (TNF)-a were observed. These results suggested that cPLA 2 a plays a protective role in progression of insulitis and development of autoimmune diabetes by suppression of TNF-a production from macrophages.

Roles of cPLA2α and arachidonic acid in cancer

“…Additional studies in cPLA 2 α-deficient mice show that its absence results in resistance to inflammation, demonstrated by suppression of ischemia-reperfusion injury of the brain [34], collagen-induced arthritis [39], inflammatory bone resorption [40], pulmonary inflammatory responses [41,42], HCl-or endotoxin-induced acute respiratory distress syndrome [42], and experimental autoimmune encephalomyelitis [43]. In contrast, the absence of cPLA 2 α has been shown to exacerbate autoimmune diseases such as type-1 diabetes [44]. In one such study, it was shown that non-obese diabetic (NOD) mice deficient in cPLA 2 α developed severe insulitis and a higher incidence of diabetes compared to their wild-type littermates [44].…”

“…In one such study, it was shown that non-obese diabetic (NOD) mice deficient in cPLA 2 α developed severe insulitis and a higher incidence of diabetes compared to their wild-type littermates [44]. Furthermore, peritoneal macrophages isolated from NOD mice with a cPLA 2 α deficiency produced significantly more TNF-α in response to LPS treatment, suggesting that cPLA 2 α may be involved in a negative feedback loop regulating TNF-α synthesis [44].…”

Cytosolic phospholipase A2: physiological function and role in disease

“…The results indicate that cPLA 2 ␣ mediates osteoclastic bone resorption due to endotoxininduced PGE 2 production by osteoblasts. The role of cPLA 2 ␣ in regulating autoimmune disease in nonobese diabetic (NOD) mice has also been investigated ( 230 ). NOD mice spontaneously develop autoimmune diabetes that has similarities to human type 1 diabetes.…”

Cytosolic phospholipase A2: Biochemical properties and physiological roles

“…Autoimmune diabetes (38) some abnormalities in renal physiology, reproduction, and synaptic plasticity. Although the molecular mechanisms underlying these phenotypes and the identification of one or multiple critical mediators downstream of cPLA 2 a remain to be clarified, these observations suggest that cPLA 2 a inhibitors might be promising drugs for treatment of various inflammatory and allergic disorders.…”