Upregulated expression of toll-like receptor 4 in monocytes correlates with severity of acute cerebral infarction.
In the present study, we observed the expression of toll-like receptor 4 (TLR4) and its downstream signal pathway in peripheral blood monocytes (PBMs) from patients with acute cerebral infarct (ACI). The expression of TLR4 and MyD88 by PBMs was determined by flow cytometry and reverse transcriptase-polymerase chain reaction, and nuclear factor-kappaB (NF-kappaB) activity was detected by electrophoretic mobility shift assay. Ischemia/reperfusion injury-induced cerebral edema, infarction area, and neurologic impairment scores were determined in MyD88 gene knockout mice. The results indicated a significant increase in circulating TLR4(+) monocytes in ACI patients as compared with the control group and the transient ischemia attack (TIA) group. This change paralleled an elevation in TLR4mRNA transcription and serum tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 in the ACI and TIA groups. Correlation analysis showed TLR4 expression to significantly correlate with cytokine levels and stroke severity. MyD88mRNA differed insignificantly among the three groups. Compared with wild-type mice, 6 h of cerebral ischemia followed by 24 h of reperfusion did not significantly change cerebral edema, cerebral infarction area, and neurologic impairment scores in MyD88 gene knockout mice. Compared with the control group, serum heat shock protein (HSP) 60 increased significantly in the ACI and TIA groups, leading to NF-kappaB activation in TLR4/CD14-transfected HEK293 cells. It is suggested that upregulated TLR4 expression on PMBs may act as one of the peripheral mechanisms of inflammatory injury after ACI. Moreover, circulating HSP60 may be a ligand for TLR4, which is involved in the peripheral mechanism of inflammatory injury after ACI, possibly through an MyD88-independent signal pathway.
Yang
Qing-wu
QW
Department of Neurology, Daping Hospital, The Third Military Medical University, Yuzhong District, Chongqing, China. Yangqwmlys@hotmail.com
Li
Jing-cheng
JC
Lu
Feng-lin
FL
Wen
Ai-qing
AQ
Xiang
Jing
J
Zhang
Li-li
LL
Huang
Zhi-yu
ZY
Wang
Jing-zhou
JZ
D000818:Animals; D001929:Brain Edema; D002545:Brain Ischemia; D016022:Case-Control Studies; D002544:Cerebral Infarction / Q000473:pathology*; D016207:Cytokines / Q000032:analysis; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D012720:Severity of Illness Index; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics*
D016207:Cytokines; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4