There is convincing evidence that cytokines are involved in the inflammatory response following cerebral ischemia, but the interactions among the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in the early stage of ischemic reperfusion are not yet completely understood. In this study, we examined the early mRNA expressions of pro-inflammatory cytokines in the ischemic hippocampus after 30 min of bilateral common carotid artery occlusion in C57BL/6J wild-type (WT) and TNF-α, IL-1α/β or IL-6 gene knockout (KO) mice utilizing real-time polymerase chain reaction. The mRNA expressions of the pro-inflammatory cytokines TNF-α, IL-6 and IL-1β were significantly induced in ischemic WT mice compared with in the sham-operated mice. These increases peaked at 3 to 24 h for TNF-α, at 12 h for IL-1β, and at 6 to 24 h for IL-6 after ischemia. The pattern of temporal expression of the cytokine mRNAs in ischemic gene KO mice, however, differed from that in WT mice. The TNF-α mRNA expression showed a similar temporal expression pattern in IL-6 KO mice compared to in WT mice following ischemic reperfusion, and the levels at all time points were lower than in WT mice. The IL-1β mRNA level was very low in ischemic TNF-α KO mice and IL-6 KO mice in spite of a small peak observed in both at 24 h. The IL-6 mRNA level was significantly upregulated at all time points in both ischemic WT and TNF-α KO mice; however, the peak was delayed by 12-h in IL-1α/β KO mice. In conclusion, the present study indicates that the rapid increases in cytokine levels are interdependent, interactive, and possibly modulate each other in the mouse hippocampus after transient global ischemia.
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