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

Brant, Kelly A.; Fabisiak, James P.

doi:10.1165/rcmb.2007-0314oc

Cited by 21 publications

(20 citation statements)

References 51 publications

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“…In our previous studies dissecting the signaling mechanisms responsible for Ni and MALP-2 synergistic amplification of CXC chemokines, such as IL-8/CXCL8, we observed fundamental roles for hypoxia-inducible factor 1α (HIF-1α) and cyclooxygenase 2 (COX-2) in mediating IL-8 release from HLF (Brant and Fabisiak, 2008; Brant and Fabisiak, 2009). It was important, therefore, to determine if Ni and MALP-2 interact via similar mechanisms to direct IL-6 release.…”

Section: Resultsmentioning

confidence: 99%

“…In order to determine if MAPKs or PI3K were involved on the upstream activation of HIF-1α and COX-2 signaling, we measured whether the various kinase inhibitors could alter the accumulation of HIF-1α protein and subsequent induction of COX-2 expression that we previously observed in HLF co-exposed to Ni and MALP-2 (Brant and Fabisiak, 2008; Brant and Fabisiak, 2009). Figure 12A shows the effects of U0126 and SB203580 on HIF-1α accumulation and COX-2 expression in HLF treated with combined Ni and MALP-2.…”

Section: Resultsmentioning

confidence: 99%

“…Macrophage activating lipopeptide-2 (MALP-2), a Toll-like receptor-2 (TLR-2) agonist derived from Mycoplasma fermentans , could recapitulate the effects of live infection suggesting an interaction (or a “cross-talk”) between TLR-2-dependent and Ni-dependent signaling processes. The specific mechanisms responsible for this interaction on IL-6 remain to be identified, although synergistic interactions between Ni and MALP-2 on release of IL-8 utilized hypoxia inducible factor 1α (HIF-1α)- and cyclooxygenase 2 (COX-2)-dependent signaling pathways (Brant and Fabisiak, 2008; Brant and Fabisiak, 2009). …”

Section: Introductionmentioning

confidence: 99%

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Multiple protein kinase pathways mediate amplified IL-6 release by human lung fibroblasts co-exposed to nickel and TLR-2 agonist, MALP-2

Gao

Brant

Ward

et al. 2010

Toxicology and Applied Pharmacology

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multiple protein kinase pathways mediate amplified IL-6 release by human lung fibroblasts co-exposed to nickel and TLR-2 agonist, MALP-2

Gao

Brant

Ward

et al. 2010

Toxicology and Applied Pharmacology

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“…RNA was extracted using RT 2 qPCR-Grade RNA Isolation Kit (SuperArray Bioscience Corporation, Frederick, MD), and 1.0-μg of RNA was converted to cDNA using RT 2 Profiler PCR Array System. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed using GeneAmp PCR System 2400 (Perkin Elmer, Boston, MA) and genes associated with TLR2 signaling (such as myeloid differentiation factor 88 [MyD88], interleukin-1 receptor associated kinases [IRAK], and TNF receptor-associated factor 6 [TRAF6]) were assessed using the iCycler instrument (Biorad Laboratories, Hercules, CA) [8]. …”

Section: Methodsmentioning

confidence: 99%

The R753Q Polymorphism Abrogates Toll‐Like Receptor 2 Signaling in Response to Human Cytomegalovirus

2009

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Toll-like receptor 2 (TLR2) serves as a pattern recognition receptor that signals the presence of cytomegalovirus. Herein, we report that R753Q polymorphism paralyzes TLR2-mediated immune signaling in cells exposed to cytomegalovirus glycoprotein B. This immunologic impairment could serve as a biologic mechanism underlying the association between TLR2 R753Q polymorphism and cytomegalovirus disease in humans.

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“…Total RNA was reverse transcribed and the cDNA was amplified by real-time PCR (MJ Research Opticon 2; Bio-Rad Laboratories, Hercules, CA), as described previously (29). The following primers sets were used: MT2A (forward, 59-CAACCTGTCCCGACTCTAGC-39; reverse, 59-TGGAAGTCGC GTTCTTTACAT-39); Ribosomal protein L13A (RPL13A) (forward, 59-CGAGGTTGGCTGGAAGTACC-39; reverse, 59-ATTCCAGG GCAACAATGGAG) (gift from K. Brant [30]); Mt1 (forward, 59-CA CCAGATCTCGGAATGGAC-39; reverse, 59-AGGAGCAGCAGC TCTTCTTG); b-actin (forward, 59-GGGACCTGACCGACTACC TC-39; reverse, 59-GGGCGATGATCTTGATCTTC-39). Gene expression was quantified using standard curves for the respective cDNA products.…”

Section: Rna Isolation and Real-time Rt-pcrmentioning

confidence: 99%

Nickel Mobilizes Intracellular Zinc to Induce Metallothionein in Human Airway Epithelial Cells

Nemec

Leikauf²,

Pitt³

et al. 2009

Am J Respir Cell Mol Biol

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We recently reported that induction of metallothionein (MT) was critical in limiting nickel (Ni)-induced lung injury in intact mice. Nonetheless, the mechanism by which Ni induces MT expression is unclear. We hypothesized that the ability of Ni to mobilize zinc (Zn) may contribute to such regulation and therefore, we examined the mechanism for Ni-induced MT2A expression in human airway epithelial (BEAS-2B) cells. Ni induced MT2A transcript levels and protein expression by 4 hours. Ni also increased the activity of a metal response element (MRE) promoter luciferase reporter construct, suggesting that Ni induces MRE binding of the metal transcription factor (MTF-1). Exposure to Ni resulted in the nuclear translocation of MTF-1, and Ni failed to induce MT in mouse embryonic fibroblasts lacking MTF-1. As Zn is the only metal known to directly bind MTF-1, we then showed that Ni increased a labile pool of intracellular Zn in cells as revealed by fluorescence-activated cell sorter using the Zn-sensitive fluorophore, FluoZin-3. Ni-induced increases in MT2A mRNA and MRE-luciferase activity were sensitive to the Zn chelator, TPEN, supporting an important role for Zn in mediating the effect of Ni. Although neither the source of labile Zn nor the mechanism by which Ni liberates labile Zn was apparent, it was noteworthy that Ni increased intracellular reactive oxygen species (ROS). Although both N-acetyl cysteine (NAC) and ascorbic acid (AA) decreased Ni-induced increases in ROS, only NAC prevented Ni-induced increases in MT2A mRNA, suggesting a special role for interactions of Ni, thiols, and Zn release.

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

Cited by 21 publications

References 51 publications

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

The R753Q Polymorphism Abrogates Toll‐Like Receptor 2 Signaling in Response to Human Cytomegalovirus

Nickel Mobilizes Intracellular Zinc to Induce Metallothionein in Human Airway Epithelial Cells

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