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J. Biol. Chem., Vol. 278, Issue 33, 31177-31183, August 15, 2003

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Persistent Protease-activated Receptor 4 Signaling Mediates Thrombin-induced Microglial Activation^*

Zhiming Suo   ¶, Min Wu , Bruce A. Citron  ||, Chenhua Gao || and Barry W. Festoff  ** 

From the Laboratory for Alzheimer's Disease & Aging Research, the ^||Molecular Biology Research Laboratory, the ^**Neurobiology Research Laboratory, Veterans Affairs Medical Center, Kansas City, Missouri 64128, and the Departments of Neurology and Pharmacology, Toxicology, and Therapeutics, University of Kansas School of Medicine, Kansas City, Kansas 66170

We have previously reported that thrombin, the ultimate serine protease in the coagulation cascades, is a proinflammatory agent that causes proliferation and activation of brain microglial cells. However, participation of its principal receptor, the protease-activated receptor 1 (PAR1) appears to be limited to promoting microglial proliferation and not induction of inflammatory mediators. In the present study, we now report that thrombin action in promoting inflammatory mediators from brain microglia is mediated through another thrombin receptor, PAR4. Here we show that the PAR4 agonist peptide (PAR4AP, GYPGKF), but not the PAR1AP (TRAP, SFLLRN), induced tumor necrosis factor- (TNF-) production not only in cultured murine microglial cells in vitro but also in rat cortex in vivo. Down-regulation of PAR4 expression in microglial cultures by a specific antisense, but not a sense, oligonucleotide reduced PAR4AP-induced TNF-. Mechanistic studies indicated that, in comparison with PAR1 signaling, prolonged increase of [Ca²⁺]_i and phosphorylation of p44/42 mitogen-activated protein kinases, as well as NFB activation may be responsible for PAR4AP-induced TNF- production in microglia. Taken together, these results demonstrate that PAR4 activation mediates the potentially detrimental effects of thrombin on microglia, implying that perspectives of exploiting PAR1 as a potential anti-inflammatory target should be shifted toward PAR4 as a much more specific therapeutic target in brain inflammatory conditions associated with neurotrauma and neurodegenerations.

Received for publication, February 28, 2003 , and in revised form, May 2, 2003.

^* This work was supported by the Medical Research and Development Service, Department of Veterans Affairs (to Z. S., B. A. C., and B. W. F.), a grant (to Z. S.) from the Missouri Alzheimer's Research Fund, a grant (to B. A. C.) from the Alzheimer's Association and resources from the Midwest Biomedical Research Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Laboratory for Alzheimer's Disease & Aging Research, Veterans Affairs Medical Center, 4801 Linwood Blvd., Kansas City, MO 64128. Tel.: 816-861-4700 (ext. 7084); Fax: 816-922-3375; E-mail: zsuo{at}kumc.edu.

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