title: Nickel alterations of TLR2-dependent chemokine profiles in lung fibroblasts are mediated by COX-2.
abstract: Particulate matter air pollution (PM) has been linked with chronic respiratory diseases. Real-life exposures are likely to involve a mixture of chemical and microbial stimuli, yet little attention has been paid to the potential interactions between PM components (e.g., Ni) and microbial agents on the development of inflammatory-like conditions in the lung. Using the Toll-like receptor (TLR)-2 agonist MALP-2 as a lipopeptide relevant to microbial colonization, we hypothesized that nickel sensitizes human lung fibroblasts (HLF) for microbial-driven chemokine release through modulation of TLR signaling pathways. NiSO(4) (200 muM) synergistically enhanced CXCL8, yet antagonized CXCL10 mRNA expression and protein release from HLF in response to MALP-2. RT(2)-PCR pathway-focused array results indicated that NiSO(4) exposure did not alter the expression of TLRs or their downstream signaling mediators, yet significantly increased the expression of cyclooxygenase 2 (COX-2). Moreover, when NiSO(4) was given in combination with MALP-2, there was an amplified induction of COX-2 mRNA and protein along with its metabolic product, PGE2, in HLF. The COX-2 inhibitor, NS-398, attenuated NiSO(4) and MALP-2-induced PGE2 and CXCL8 release and partially reversed the NiSO(4)-dependent inhibition of MALP-2-induced CXCL10 release from HLF. These data indicate that NiSO(4) alters the pattern of TLR-2-dependent chemokine release from HLF via a COX-2-mediated pathway. The quantitative and qualitative effects of NiSO(4) on microbial-driven chemokine release from HLF shed new light on how PM-derived metals can exacerbate respiratory diseases.
authors: University of Pittsburgh Graduate School of Public Health, Department of Environmental and Occupational Health, Bridgeside Point, 100 Technology Drive, Room 327, BRIDG, Pittsburgh, PA 15219-3130, USA. kab124@pitt.edu
authors: Kelly A
authors: KA
authors: Brant
authors: James P
authors: JP
authors: Fabisiak
mesh_terms: D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D055666:Lipopeptides; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009532:Nickel / Q000009:adverse effects*; D009842:Oligopeptides / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000502:physiology*
chemical_list: C114753:CXCL10 protein, human; C508606:CXCL8 protein, human; D054357:Chemokine CXCL10; D018925:Chemokines; D052246:Cyclooxygenase 2 Inhibitors; D016209:Interleukin-8; D055666:Lipopeptides; D009842:Oligopeptides; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; C029938:nickel sulfate; D009532:Nickel; C106335:macrophage stimulatory lipopeptide 2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human