ISSN:
1524-475X
Quelle:
Blackwell Publishing Journal Backfiles 1879-2005
Thema:
Medizin
Notizen:
Wound healing involves a series of overlapping, highly coordinated events. Macrophages play multiple crucial roles in these processes including the secretion of chemokines. Interleukin-8 (IL-8) is an inducible chemokine that is expressed in a variety of cell types present at the wound site, including macrophages, and is known to contribute to chemotaxis, angiogenesis, and tissue remodeling during wound healing. One of the potent natural inducers of IL-8 is thrombin, a multifunctional enzyme that is released upon wounding. Little is known about how this enzyme stimulates IL-8 in macrophages. Therefore, we used a variety of cellular and molecular approaches to investigate the signal transduction mechanism of thrombin-induced IL-8 expression in THP-1-differentiated macrophages. We show that stimulation of IL-8 by thrombin occurs in a rapid manner that is time- and dose-dependent and can be abolished by addition of hirudin, a specific inhibitor of thrombin. At the mRNA level, IL-8 peaks ∼4 hrs after treatment and declines by 9 hrs. A variety of inhibitors were used to delineate the signal transduction pathways leading to IL-8 expression. Application of AG1478, a potent EGFR inhibitor, abolishes thrombin-induced IL-8 production suggesting EGFR transactivation. We further show that MEK1/2 and p38 are important signal mediators; their inhibition abolishes IL-8 production. Contrarily, PKC inhibitors do not abolish, but rather enhance production of IL-8, whereas activators inhibit the thrombin stimulation, suggesting that PKC is a negative regulator of IL-8 expression. In summary, these results suggest that thrombin stimulates IL-8 expression by transactivating the EGFR leading to activation of MEK1/2 and p38, and that PKC is a negative regulator of this stimulation process.
Materialart:
Digitale Medien
URL:
http://dx.doi.org/10.1111/j.1067-1927.2004.0abstractxm.x
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