The role of MAPK in Kupffer cell toll-like receptor (TLR) 2-, TLR4-, and TLR9-mediated signaling following trauma-hemorrhage.

Abstract

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 approximately 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-alpha, 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-alpha, 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-alpha 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-alpha 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.

• Authors: Bjoern M Thobe, Michael Frink, Frank Hildebrand, Martin G Schwacha, William J Hubbard, Mashkoor A Choudhry, Irshad H Chaudry
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 210 Issue 3 Pg. 667-75 (Mar 2007) ISSN: 0021-9541 [Print] United States
• PMID: 17117477 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright 2006 Wiley-Liss, Inc.

Chemical References

• Ccl2 protein, mouse
• Chemokine CCL2
• Interleukin-6
• Lipopolysaccharides
• Tlr2 protein, mouse
• Tlr4 protein, mouse
• Tlr9 protein, mouse
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Toll-Like Receptor 9
• Tumor Necrosis Factor-alpha
• Zymosan
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Cells, Cultured
• Chemokine CCL2 (metabolism)
• Hemorrhage (pathology, physiopathology)
• Interleukin-6 (metabolism)
• JNK Mitogen-Activated Protein Kinases (physiology)
• Kupffer Cells (pathology, physiology)
• Lipopolysaccharides (pharmacology)
• Male
• Mice
• Mice, Inbred C3H
• Mitogen-Activated Protein Kinase 3 (physiology)
• Mitogen-Activated Protein Kinases (metabolism)
• Signal Transduction (physiology)
• Toll-Like Receptor 2 (agonists, physiology)
• Toll-Like Receptor 4 (agonists, physiology)
• Toll-Like Receptor 9 (agonists, physiology)
• Tumor Necrosis Factor-alpha (metabolism)
• Wounds and Injuries (pathology, physiopathology)
• Zymosan (pharmacology)
• p38 Mitogen-Activated Protein Kinases (physiology)