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.

Glycyrrhizic Acid Prevents Sepsis-Induced Acute Lung Injury and Mortality in Rats

“…p38 MAPK and JNK are two important family members that regulate the release of inflammatory mediators (Silvers et al 2003). Lipopolysaccharide promotes the production and release of a large number of inflammatory mediators through the activation of MAPK, and this has been shown to be important in the onset and progression of ALI (Thobe et al 2007;Asaduzzaman et al 2008). In our studies, NF-κB, JNK, and p38 MAPK were all elevated in ALI, and GA inhibited their expressions, offering a protective effect against sepsis.…”

Complement Component C5a Mediates Hemorrhage-Induced Intestinal Damage

“…Previous studies have illustrated that monocytes treated with C5a produce IL-6 (37). Other studies have shown that hemorrhage increases KC, MCP-1, IL-6 and IL-10 serum concentrations in a TLR4-dependent manner (22,38,39). In addition, Meng et.al.…”

“…Many animal models of hemorrhage involve rats and include traumatic injury (19)(20)(21)(22)(23)(24) and the use of heparin (3,16) which complicates determination of the complement activation factors. In addition, rat models of hemorrhagic shock preclude the use of genetically modified animals.…”

Cellular Signaling Molecules Associated with Peptidoglycan-Induced CCL3 Up-Regulation

“…PGN elevates phosphorylation of MAPKs, and MAPKs mediate chemokine production in TLR2, 4, and 9 signaling, which indicates the involvement of the kinases in CCL3 expression (Thobe et al, 2007;Lee et al, 2011). Appropriately, we investigated if MAPKs played roles in the expression of the chemokine.…”