Involvement of cytokine production in pathogenesis of transient cerebral ischemic damage

The contribution of cytokines in an inflammatory cascade on cerebral reperfusion injury are characterized as typical phases; leukocytes invision, microglial activation, and remodeling. Within 1-2 days, IL-1 (interleukin-1) and TNF (tumour necrosis factor) induce the expression of adhesion molecules that cause leukocytes adhere to endothelial cells. IL-8 (CINC; cytokine-induced neutrophil chemoattractant) is a well-known chemokine that promotes invasion of these leukocytes into brain parenchyma. The activation of proteases and free radical formation by invading neutrophils induces lipid peroxidation and subsequently neuronal damage. From 2 to 7 days, microglia is activated mainly in the "reactive zone" at the boundary of the infarct, and secrete IL-1 and TNF. These cytokines induce astroglial proliferation and production of trophic factors by astroglia to limit the neuronal damage. However, excess astrogliosis exert a negative effect on neuroregeneration. From 7 to 30 days, phagocytic macrophages are observed in the core of infarction sites. The macrophages release a number of cytophylactic agents including proteases and superoxide anions to degrade the damaged areas. TGF-beta and basic FGF (fibroblast growth factor) from glial cells and macrophages induce angiogenesis to discard the debris for subsequent remodeling. These complicated cascade after cerebral reperfusion injury are indeed controlled by cytokines: IL-1 and TNF are considered to be primary mediators that work in concert with IL-8 and growth factors to initiate and regulate the local inflammation in the brain.