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FE Kruse, L You; Toll-like Receptor 4 Mediates Intracellular ASignals for Lipoteichoic Acid-induced Expression of CXC Chemokines in the Cornea . Invest. Ophthalmol. Vis. Sci. 2002;43(13):857.
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Purpose: Toll-like receptor 4 (TLR 4) is a membrane receptor specific for gram-positive bacterial cell wall component e.g. lipoteichoic acid (LTA). It was previously shown that LTA induces the activation of ERK pathway and the transcription of chemokines GRO-a and IL-8 in corneal keratocytes. To fully understand the molecular mechanism of corneal inflammation, we investigate the role of TLR 4 as well as focal adhesion kinase (FAK) in LTA-induced expression of GRO-a and IL-8. Methods: Human corneal keratocytes were cultured in the presence of LTA from Staphylococcus aureus. The transcription of TLR 4 and MD-2, a TLR 4-associated protein to discriminate LTA, were detected by RT-PCR. The formation of TLR 4 and FAK complex were evaluated by coimmunoprecipitation and western blots. The distinctive tyrosine phosphorylation sites in FAK for LTA-induced signaling were characterized by phosphospecific antobodies against FAK. Protein kinase inhibitors were used to identify LTA-induced signaling for the expression of chemokines. Results: The transcription of TLR 4 and MD-2 was detectable in ex vivo corneal stroma and cultured keratocytes. The formation of TLR 4 and FAK complex is time-dependently induced by LTA and inhibited by herbimycin A. Two specific tyrosine phosphorylation sites of FAK were activated in response to LTA. The LTA-induced transcription and expression of GRO-a and IL 8 are inhibited by PD 98059 and herbimycin A. Conclusion: LTA-induced expression of chemokines in corneal keratocytes is mediated by TLR-4-FAK signaling. TLR 4 plays a crucial role in gram positive bacteria-induced inflammatory process in the cornea. FAK seems very important to mediate signals from membrane receptors to downstream effector e.g. ERK.
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