Interleukin-18 Expression after Focal Ischemia of the Rat Brain: Association with the Late-Stage Inflammatory Response

Abstract

Interleukin-18, previously designated interferon γ-inducing factor, is a proinflammatory cytokine structurally related to interleukin-1β and is therefore considered a member of the growing family of interleukin-1–like cytokines. Both interleukin-18 and −1β are synthesized as inactive precursors that necessitate cleavage by caspase-1 for functional activity. In this study, the authors analyzed the expression pattern of interleukin-18, −1β, and caspase-1 in focal brain ischemia induced in rats either by permanent middle cerebral artery occlusion or by photothrombosis of cortical microvessels. Using reverse transcriptase-polymerase chain reaction, they found a delayed increase of interleukin-18 mRNA starting at 48 hours and reaching its peak between 7 and 14 days after ischemia. In contrast, interleukin-1β mRNA peaked within 16 hours and was downregulated thereafter. The time course of caspase-1 mRNA expression paralleled that of interleukin-18, but not of interleukin-1β mRNA. Immunocytochemically, interleukin-18 expression was localized to ED1-positive phagocytic microglia/macrophages infiltrating the necrotic lesion between 3 and 6 days after ischemia. In contrast, interleukin-1β immunoreactivity was expressed by ramified microglia in the infarct border zone and remote ipsilateral cortex during the first 16 hours postlesion. Induction of interleukin-18 was not accompanied by detectable expression of interferon-γ mRNA. Their data show spatial and temporal diversity in interleukin-1 and −18 cytokine family expression in brain ischemia, and suggest a role of the interleukin-18/caspase-1 pathway in late-stage inflammatory responses to focal brain ischemia.