Integration of cytokine biology and lipid metabolism in stroke.
Cytokines regulate the innate and adaptive immune responses and are pleiotropic, redundant and multifunctional. Expression of most cytokines, including TNF-alpha and IL-1alpha/beta, is very low in normal brain. Metabolism of lipids is of particular interest due to their high concentration in the brain. Inflammatory response after stroke suggests that cytokines (TNF-alpha, IL-1alpha/beta, IL-6), affect the phospholipid metabolism and subsequent production of eicosanoids, ceramide, and ROS that may potentiate brain injury. Phosphatidylcholine and sphingomyelin are source for lipid messengers. Sphingomyelin synthase serves as a bridge between metabolism of glycerolipids and sphingolipids. TNF-alpha and IL-1alpha/beta can induce phospholipases (A2, C, and D) and sphingomyelinases, and concomitantly proteolyse phosphatidylcholine and sphingomyelin synthesizing enzymes. Together, these alterations contribute to loss of phosphatidylcholine and sphingomyelin after stroke that can be attenuated by inhibiting TNF-alpha or IL-1alpha/beta signaling. Inflammatory responses are instrumental in the formation and destabilization of atherosclerotic plaques. Secretory PLA2 IIA is found in human atherosclerotic lesions and is implicated in initiation, progression and maturation of atherosclerosis, a risk factor for stroke. Lipoprotein-PLA2, part of apolipoprotein B-100 of LDL, plays a role in vascular inflammation and coronary endothelial dysfunction. Cytokine antagonism attenuated secretory PLA2 IIA actions, suggesting cytokine-lipid integration studies will lead to new concepts contributing to bench-to-bedside transition for stroke therapy.
Adibhatla
Rao Muralikrishna
RM
Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792-3232, USA. adibhatl@neurosurg.wisc.edu
Dempsy
Robert
R
Hatcher
James Franklin
JF
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008074:Lipoproteins / Q000378:metabolism; D008954:Models, Biological; D012313:RNA / Q000378:metabolism; D017382:Reactive Oxygen Species; D012307:Risk Factors; D020521:Stroke / Q000378:metabolism*
D016207:Cytokines; D008055:Lipids; D008074:Lipoproteins; D017382:Reactive Oxygen Species; D012313:RNA