The role of MAPK in Kupffer cell toll-like receptor (TLR) 2-, TLR4-, and TLR9-mediated signaling following trauma-hemorrhage
Article first published online: 21 NOV 2006
Copyright © 2006 Wiley-Liss, Inc.
Journal of Cellular Physiology
Volume 210, Issue 3, pages 667–675, March 2007
How to Cite
Thobe, B. M., Frink, M., Hildebrand, F., Schwacha, M. G., Hubbard, W. J., Choudhry, M. A. and Chaudry, I. H. (2007), The role of MAPK in Kupffer cell toll-like receptor (TLR) 2-, TLR4-, and TLR9-mediated signaling following trauma-hemorrhage. J. Cell. Physiol., 210: 667–675. doi: 10.1002/jcp.20860
- Issue published online: 27 DEC 2006
- Article first published online: 21 NOV 2006
- Manuscript Accepted: 9 AUG 2006
- Manuscript Received: 28 JUL 2006
- NIH. Grant Numbers: R01 GM 37127, K02 AI049960
Vol. 225, Issue 3, 915, Article first published online: 15 DEC 2010
Severe injury deranges immune function and increases the risk of sepsis and multiple organ failure. Kupffer cells play a major role in mediating posttraumatic immune responses, in part via different Toll-like receptors (TLR). Although mitogen-activated protein kinases (MAPK) are key elements in the TLR signaling pathway, it remains unclear whether the activation of different MAPK are TLR specific. Male C3H/HeN mice underwent midline laparotomy (i.e., soft tissue injury), hemorrhagic shock (MAP ∼35 mm Hg for 90 min), and resuscitation. Kupffer cells were isolated 2 h thereafter, lysed and immunoblotted with antibodies to p38, ERK1/2, or JNK proteins. In addition, cells were preincubated with specific inhibitors of p38, ERK1/2, or JNK MAPK followed by stimulation with the TLR2 agonist, zymosan; the TLR4 agonist, LPS; or the TLR9 agonist, CpG DNA. Cytokine (TNF-α, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and KC) production was determined by cytometric bead array after 24 h in culture. MAPK activity as well as TNF-α, MCP-1, and KC production by Kupffer cells were significantly increased following trauma-hemorrhage. TLR4 activation by LPS stimulation increased the levels of all measured cytokines. CpG-stimulated TLR9 signaling increased TNF-α and IL-6 levels; however, it had no effect on chemokine production. Selective MAPK inhibition demonstrated that chemokine production was mediated via p38 and JNK MAPK activation in TLR2, -4, and -9 signaling. In contrast, TNF-α and IL-6 production was differentially regulated by MAPK depending on the TLR pathway stimulated. Thus, Kupffer cell TLR signaling employs different MAPK pathways in eliciting cytokine and chemokine responses following trauma-hemorrhage. J. Cell. Physiol. 210: 667–675, 2007. © 2006 Wiley-Liss, Inc.