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Am J Physiol Cell Physiol (March 29, 2006). doi:10.1152/ajpcell.00076.2006
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Submitted on February 16, 2006
Accepted on March 24, 2006

Src Family Kinases Regulate p38 MAPK-Mediated IL-6 Production in Kupffer Cells Following Hypoxia

Bjoern M. Thobe1, Michael Frink1, Mashkoor A. Choudhry1*, Martin G. Schwacha1, Kirby I. Bland1, and Irshad H. Chaudry1

1 Center for Surgical Research, University of Alabama at Birmingham, Birmingham, Alabama, United States; Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States

* To whom correspondence should be addressed. E-mail: choudhry{at}uab.edu.

Tissue hypoxia is a common sequel of trauma-hemorrhage but can occur even without blood loss under hypoxic conditions. Although hypoxia is known to upregulate Kupffer cells (KC) to release cytokines, the precise mechanism of release remains unknown. We hypothesized that Src family kinases play a role in mediating KC mitogen-activated protein kinase (MAPK) signaling and their cytokine production after hypoxia. Male C3H/HeN mice received either Src inhibitor PP1 (1.5 mg/kg BW) or vehicle 1 h prior to hypoxia. KC were isolated 1 h after hypoxia, lysed and immunoblotted with antibodies to Src, p38, ERK1/2 or JNK proteins. In addition, KC were cultured to measure IL-6 and MCP-1 production. Hypoxia produced a significant increase in KC Src and MAPK (p38, ERK, JNK) activity compared to normoxic controls. This was associated with an increase in IL-6 and MCP-1 production. Treatment with PP1 abolished the increase in KC Src activation as well as p38 activity. However, PP1 did not prevent the increase in KC ERK1/2 or JNK phosphorylation. Furthermore, administration of PP1 prevented the hypoxia-induced increase in IL-6 but not MCP-1 release by KC. Additional in vitro results suggest that p38 but not ERK1/2 or JNK are critical for KC IL-6 production. In contrast, the production of MCP-1 by KC was found to be independent of MAPK. Thus, hypoxia increases KC IL-6 production by p38 MAPK activation via Src-dependent pathway. Src kinases may therefore be a novel therapeutic target for preventing immune dysfunction following low flow conditions in trauma patients.




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