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Nickel Alterations of TLR2-Dependent Chemokine Profiles in Lung Fibroblasts Are Mediated by COX-2

¹ Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Kelly Brant, M.P.H., Ph.D., 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. E-mail: kab124{at}pitt.edu

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. NiSO₄ (200 µM) synergistically enhanced CXCL8, yet antagonized CXCL10 mRNA expression and protein release from HLF in response to MALP-2. RT²-PCR pathway-focused array results indicated that NiSO₄ 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 NiSO₄ 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 NiSO₄ and MALP-2–induced PGE2 and CXCL8 release and partially reversed the NiSO₄-dependent inhibition of MALP-2–induced CXCL10 release from HLF. These data indicate that NiSO₄ alters the pattern of TLR-2–dependent chemokine release from HLF via a COX-2–mediated pathway. The quantitative and qualitative effects of NiSO₄ on microbial-driven chemokine release from HLF shed new light on how PM-derived metals can exacerbate respiratory diseases.

Key Words: COX-2 • nickel • inflammation • chemokines • fibroblasts

CLINICAL RELEVANCE This study examines how metals such as nickel can sensitize cells to microbial-driven inflammation in the lung. These findings will increase our understanding of how environmental exposures interact to modulate pulmonary inflammation.