Exposure to zinc-laden particulate matter in ambient and occupational settings has been associated with proinflammatory responses in the lung. IL-8 is an important proinflammatory cytokine in the human lung and is induced in human airway epithelial cells exposed to zinc. In this study, we examined the cellular mechanisms responsible for Zn(2+)-induced IL-8 expression. Zn(2+) stimulation resulted in pronounced increases in both IL-8 mRNA and protein expression in the human airway epithelial cell line (BEAS-2B). IL-8 promoter activity was significantly increased by Zn(2+) exposure in BEAS-2B cells, indicating that Zn(2+)-induced IL-8 expression is transcriptionally mediated. Mutation of the activating protein (AP)-1 response element in an IL-8 promoter-enhanced green fluorescent protein construct reduced Zn(2+)-induced IL-8 promoter activity. Moreover, Zn(2+) exposure of BEAS-2B cells induced the phosphorylation of the AP-1 proteins c-Fos and c-Jun. We observed that Zn(2+) exposure induced the phosphorylation of ERK, JNK, and p38 MAPKs, whereas inhibition of ERK or JNK activity blocked IL-8 mRNA and protein expression in BEAS-2B cells treated with Zn(2+). In addition, we investigated the role of protein tyrosine phosphatases in the activation of signaling by Zn(2+). Zn(2+) treatment inhibited ERK- and JNK-directed phosphatase activities in BEAS-2B cells. These results suggested that Zn(2+)-induced inhibition of phosphatase activity is an initiating event in MAPK and AP-1 activation that leads to enhanced IL-8 expression by human airway epithelial cells.
Epidemiological studies suggest that ultrafine particles contribute to particulate matter-induced adverse health effects. Interleukin (IL)-8 is an important proinflammatory cytokine in the human lung that is induced in respiratory cells exposed to a variety of environmental insults, including ambient air ultrafine particles. In this study, we examined the effect of a model ultrafine particle on IL-8 expression and the cellular mechanisms responsible for this event. Here, we report that carbonaceous ultrafine particles consisting of synthetic elemental carbon particles (UfCP) markedly increase the expression of IL-8 mRNA and protein in normal human bronchial epithelial (NHBE) cells. IL-8 promoter activity was increased by UfCP exposure in NHBE cells, indicating UfCP-induced IL-8 expression is transcriptionally regulated. IL-8 expression in NHBE is known to be regulated by nuclear factor (NF)-kappaB activation. However, UfCP did not induce inhibitory factor kappaBalpha degradation, NF-kappaB-DNA binding, or NF-kappaB-dependent promoter activity in NHBE cells, indicating that UfCP induces IL-8 expression through a mechanism that is independent of NF-kappaB activation. Additionally, we observed that UfCP exposure induces the phosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) in a biphasic manner and that the inhibition of p38 MAPK activity can block IL-8 mRNA expression induced by UfCP in NHBE cells. These results demonstrate that UfCP-induced expression of IL-8 involves a transcriptional mechanism and activation of p38 MAPK in NHBE cells.
Kawasaki disease (KD) is an acute inflammatory illness marked by coronary arteritis. However, the factors increasing susceptibility to coronary artery lesions are unknown. Because transforming growth factor (TGF)  increases elastin synthesis and suppresses proteolysis, we hypothesized that, in contrast to the benefit observed in aneurysms forming in those with Marfan syndrome, inhibition of TGF- would worsen inflammatory-induced coronary artery lesions. By using a murine model of KD in which injection of Lactobacillus casei wall extract (LCWE) induces coronary arteritis, we show that LCWE increased TGF- signaling in the coronary smooth muscle cells beginning at 2 days and continuing through 14 days, the point of peak coronary inflammation. By 42 days, LCWE caused fragmentation of the internal and external elastic lamina. Blocking TGF- by administration of a neutralizing antibody accentuated the LCWE-mediated fragmentation of elastin and induced an overall loss of medial elastin without increasing the inflammatory response. We attributed these increased pathological characteristics to a reduction in the proteolytic inhibitor, plasminogen activator inhibitor-1, and an associated threefold increase in matrix metalloproteinase 9 activity compared with LCWE alone. Therefore, our data demonstrate that in the coronary arteritis associated with KD, TGF- suppresses elastin degradation by inhibiting plasmin-mediated matrix metalloproteinase 9 activation. Thus, strategies to block TGF-, used in those with Marfan syndrome, are unlikely to be beneficial and could be detrimental.
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