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

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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. 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.

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