title: Toll-like receptor 4 activates NF-κB and MAP kinase pathways to regulate expression of proinflammatory COX-2 in renal medullary collecting duct cells.
abstract: Binding of bacterial LPS to the Toll-like receptor 4 (TLR4) complex of inner medullary collecting duct (IMCD) cells plays a central role in recognition of ascending bacterial infections and activation of proinflammatory responses. Since proinflammatory cyclooxygenase (COX)-2 is induced in IMCD cells upon LPS exposure, the present study addressed the question of whether TLR4 mediates COX-2 induction in IMCD cells and characterized the underlying signaling mechanisms. Enhanced COX-2 expression and activity in the presence of LPS was diminished by TLR4 inhibition. LPS induced a TLR4-dependent stimulation of NF-κB and the MAPKs p38, ERK1/2, and JNK. Activation of NF-κB was under negative control of JNK, as inhibition of JNK increased NF-κB activity and COX-2 expression. Phosphorylation of p38 and ERK1/2 required TLR4-dependent release of TGF-α with subsequent activation of the epidermal growth factor receptor (EGFR), whereas JNK activation was EGFR independent. Inhibition of p38 or ERK1/2 had no significant effect on LPS-induced NF-κB activation, nor on activator protein 1-, cAMP response element-, or serum response element-driven reporter constructs. However, the transcriptional regulator SP-1 appears to contribute to COX-2 expression after LPS exposure. In conclusion, these results propose that LPS mediates enhanced COX-2 expression in IMCD cells by 1) TLR4-mediated activation of the NF-κB signaling pathway, 2) TLR4-dependent release of TGF-α with subsequent activation of the EGFR and downstream MAPKs p38 and ERK1/2, and 3) TLR4-mediated, EGFR-independent activation of JNK that negatively regulates NF-κB activation.
authors.affiliation: Dept. of Physiology, Univ. of Munich, Pettenkoferstrasse 12, 80336 Munich, Germany. Christoph.Kueper@lrz.uni-muenchen.de
authors.forename: Christoph
authors.initials: C
authors.lastname: Küper
authors.forename: Franz-Xaver
authors.initials: FX
authors.lastname: Beck
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Neuhofer
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors; D000072198:ADAM17 Protein; D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D055785:Gene Knockdown Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D016329:Sp1 Transcription Factor; C493487:Tlr4 protein, mouse; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D016211:Transforming Growth Factor alpha; D051546:Cyclooxygenase 2; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein