Chemokine IL-8 induction by particulate wear debris in osteoblasts is mediated by NF-kappaB.
Chemokines, or chemotactic cytokines, are major regulators of the inflammatory response and have been identified as pathogenic factors in the periprosthetic soft tissue. Particulate wear debris induced NF-kappaB activation, the major transcriptional regulator of IL-8 and MCP-1 pro-inflammatory genes and, indeed, both IL-8 and MCP-1 chemokine gene expressions were upregulated in titanium particulate-stimulated human osteoblasts. Here, we demonstrate that phagocytosed particles activate the IL-8 gene promoter via a NF-kappaB-mediated mechanism. Transfection of a dominant negative mutant IkappaBalpha protein that cannot be serine phosphorylated led to suppression of IL-8 promoter activity. The p65/RelA NF-kappaB subunit activity was affected in both a time- and titanium particle concentration-dependent fashion. Titanium particles led to increased ERK, JNK, and p38 activation in MG-63 osteoblast cells, and IL-8 protein release was suppressed by specific inhibitors of the ERK and p38 MAPK pathways. Together, our results suggest that wear debris particles induce chemokine expression in osteoblasts via NF-kappaB-mediated transcriptional activation, which is controlled by the MAPK signal transduction pathway.
Fritz
Elizabeth A
EA
Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612, USA.
Jacobs
Joshua J
JJ
Glant
Tibor T
TT
Roebuck
Kenneth A
KA
D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000502:physiology*; D010006:Osteoblasts / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014025:Titanium / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism
D016209:Interleukin-8; D016328:NF-kappa B; D051996:Transcription Factor RelA; D004247:DNA; D014025:Titanium