Multiple protein kinase pathways mediate amplified IL-6 release by human lung fibroblasts co-exposed to nickel and TLR-2 agonist, MALP-2.
Multiple protein kinase pathways mediate amplified IL-6 release by human lung fibroblasts co-exposed to nickel and TLR-2 agonist, MALP-2.
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DOI：
10.1016/j.taap.2010.06.007
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发表时间：
2010-09-01
影响因子：
3.8
通讯作者：
Fabisiak JP
中科院分区：
文献类型：
--
作者：
Gao F;Brant KA;Ward RM;Cattley RT;Barchowsky A;Fabisiak JP
Microbial stimuli and atmospheric particulate matter (PM) interact to amplify the release of inflammatory and immune-modulating cytokines. The basis of this interaction, however, is not known. Cultured human lung fibroblasts (HLF) were used to determine whether various protein kinase pathways were involved in the release of IL-6 following combined exposure to the PM-derived metal, Ni, and M. fermentans-derived macrophage-activating lipopeptide 2 (MALP-2), a toll-like receptor 2 agonist. Synergistic release of IL-6 by MALP-2 and NiSO4 was obvious after 8 h of co-stimulation and correlated with a late phase accumulation of IL-6 mRNA. Ni and MALP-2, alone or together, all lead to rapid and transient phosphorylations of ERK1/2 and JNK/SAPK of similar magnitude. p38 phosphorylation, however, was observed only after prolonged treatment of cells with both stimuli together. A constitutive level of PI3K-dependent Akt phosphorylation remained unchanged by Ni and/or MALP-2 exposure. IL-6 induced by Ni/MALP-2 co-exposure was partially dependent on activity of HIF-1α and COX-2 as shown by targeted knockdown using siRNA. IL-6 release in response to Ni/MALP-2 was partially sensitive to pharmacological inhibition of ERK1/2, p38, and PI3K signaling. The protein kinase inhibitors had minimal or no effects on Ni/MALP-2-induced accumulation of HIF-1α protein, however, COX-2 expression and, more markedly PGE2 production, were suppressed by LY294002, SB203580, and U0126. Thus, Ni/MALP-2 interactions involve multiple protein kinase pathways (ERK1/2, p38, and PI3K) that modulate events downstream from the early accumulation of HIF-1α to promote IL-6 gene expression directly or secondarily, through COX-2-derived autocrine products like PGE2.
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DOI：
10.1073/pnas.251194298
发表时间：
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影响因子：
11.1
作者：
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影响因子：
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DOI：
10.1152/ajplung.00031.2006
发表时间：
2006-10-01
影响因子：
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作者：
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