Influence of p38MAPK inhibition on IL-1beta-stimulated human chondrocytes: a microarray approach.
Articular chondrocytes respond to extracellular influences by activating signaling pathways which change gene expression. One key signal transduction pathway of inflammatory joint disease is mediated by the p38MAPK which is known to be activated by the pro-inflammatory cytokine IL-1beta. We used the p38MAPK inhibitor SB203580 and a whole human genome microarray in an in vitro inflammation model to identify genes regulated by this pathway in human chondrocytes. We found that 1,141 genes were regulated by IL-1beta, and 646 genes were regulated by the inhibitor whereas 116 genes were co-regulated by both substances. To elucidate the overall effect of SB203580, a GoMiner pathway analysis was performed which revealed involvement of versatile biological processes. Predominantly affected terms were 'response to stimulus', 'oxygen metabolism' and 'ligase activity'. We discuss herein the relevance and function of affected fields including the involved genes and unexpected effects of p38MAPK inhibition as it relates to the context of cartilage. Our results do not predict a pro-apoptotic or cancer promoting effect and markedly extend the knowledge on p38MAPK inhibition in chondrocytes beyond primary target genes.
Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopedics, University of Ulm, Ulm, Germany.
Helga
H
Joos
Wolfgang
W
Albrecht
Stefan
S
Laufer
Rolf E
RE
Brenner
D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D016000:Cluster Analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011725:Pyridines / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D053583:Interleukin-1beta; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580