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Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions.

Mandal AK, Zhang Z, Ray R, Choi MS, Chowdhury B, Pattabiraman N, Mukherjee AB - J. Exp. Med. (2004)

Bottom Line: These effects are abrogated by recombinant UG treatment.Here we report that DP signaling is mediated via p38 mitogen-activated protein kinase, p44/42 mitogen-activated protein kinase, and protein kinase C pathways in a cell type-specific manner leading to nuclear factor-kappaB activation stimulating COX-2 gene expression.Further, we found that recombinant UG blocks DP-mediated nuclear factor-kappaB activation and suppresses COX-2 gene expression.

View Article: PubMed Central - PubMed

Affiliation: Bldg. 10, Rm. 9S241, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.

ABSTRACT
Uteroglobin (UG) is an antiinflammatory protein secreted by the epithelial lining of all organs communicating with the external environment. We reported previously that UG-knockout mice manifest exaggerated inflammatory response to allergen, characterized by increased eotaxin and Th2 cytokine gene expression, and eosinophil infiltration in the lungs. In this study, we uncovered that the airway epithelia of these mice also express high levels of cyclooxygenase (COX)-2, a key enzyme for the production of proinflammatory lipid mediators, and the bronchoalveolar lavage fluid (BALF) contain elevated levels of prostaglandin D2. These effects are abrogated by recombinant UG treatment. Although it has been reported that prostaglandin D2 mediates allergic inflammation via its receptor, DP, neither the molecular mechanism(s) of DP signaling nor the mechanism by which UG suppresses DP-mediated inflammatory response are clearly understood. Here we report that DP signaling is mediated via p38 mitogen-activated protein kinase, p44/42 mitogen-activated protein kinase, and protein kinase C pathways in a cell type-specific manner leading to nuclear factor-kappaB activation stimulating COX-2 gene expression. Further, we found that recombinant UG blocks DP-mediated nuclear factor-kappaB activation and suppresses COX-2 gene expression. We propose that UG is an essential component of a novel innate homeostatic mechanism in the mammalian airways to repress allergen-induced inflammatory responses.

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Inhibitors of p38, p44/42, and PKC suppresses DP-mediated NF-κB activation and COX-2 expression. Expression of COX-2–mRNA in BSM-2146 (A) and in NIH-3T3 (B) cells in the absence or presence of inhibitors of p38 MAPK (SB203580, 10 μM), p44/42 MAPK (PD98059, 20 μM), or PKC (BM III, 10 μM). Dose–response of NF-κBSN50 and PTDC on PGD2-stimulated COX-2 mRNA expression in BSM-2146 (C) and NIH-3T3 (D) cells. The effect of these inhibitors on NF-κB binding in BSM-2146 (E) and NIH-3T3 (F).
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fig5: Inhibitors of p38, p44/42, and PKC suppresses DP-mediated NF-κB activation and COX-2 expression. Expression of COX-2–mRNA in BSM-2146 (A) and in NIH-3T3 (B) cells in the absence or presence of inhibitors of p38 MAPK (SB203580, 10 μM), p44/42 MAPK (PD98059, 20 μM), or PKC (BM III, 10 μM). Dose–response of NF-κBSN50 and PTDC on PGD2-stimulated COX-2 mRNA expression in BSM-2146 (C) and NIH-3T3 (D) cells. The effect of these inhibitors on NF-κB binding in BSM-2146 (E) and NIH-3T3 (F).

Mentions: To determine the possible involvement of other kinase pathways in DP signaling, we treated these cells with PGD2 in the absence and presence of highly selective inhibitors of PKC (BMIII), p38 (SB203580), and p44/42 MAPK (PD98059), and determined COX-2 mRNA expression by Northern blot analysis. We found that in BSM-2146 cells the inhibitors of all three kinases suppressed PGD2-mediated stimulation of COX-2 mRNA expression at varying degrees (Fig. 5 A), suggesting that in these cells DP signaling is mediated via activation of p38 and p44/42 MAPK and PKC pathways. In contrast, PGD2-mediated stimulation of COX-2 expression in NIH-3T3 cells was inhibited only by p38 MAPK inhibitor, SB203580 (Fig. 5 B), whereas in A549 cells only the PKC-specific inhibitor (BMIII) suppressed such stimulation (not depicted).


Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions.

Mandal AK, Zhang Z, Ray R, Choi MS, Chowdhury B, Pattabiraman N, Mukherjee AB - J. Exp. Med. (2004)

Inhibitors of p38, p44/42, and PKC suppresses DP-mediated NF-κB activation and COX-2 expression. Expression of COX-2–mRNA in BSM-2146 (A) and in NIH-3T3 (B) cells in the absence or presence of inhibitors of p38 MAPK (SB203580, 10 μM), p44/42 MAPK (PD98059, 20 μM), or PKC (BM III, 10 μM). Dose–response of NF-κBSN50 and PTDC on PGD2-stimulated COX-2 mRNA expression in BSM-2146 (C) and NIH-3T3 (D) cells. The effect of these inhibitors on NF-κB binding in BSM-2146 (E) and NIH-3T3 (F).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211805&req=5

fig5: Inhibitors of p38, p44/42, and PKC suppresses DP-mediated NF-κB activation and COX-2 expression. Expression of COX-2–mRNA in BSM-2146 (A) and in NIH-3T3 (B) cells in the absence or presence of inhibitors of p38 MAPK (SB203580, 10 μM), p44/42 MAPK (PD98059, 20 μM), or PKC (BM III, 10 μM). Dose–response of NF-κBSN50 and PTDC on PGD2-stimulated COX-2 mRNA expression in BSM-2146 (C) and NIH-3T3 (D) cells. The effect of these inhibitors on NF-κB binding in BSM-2146 (E) and NIH-3T3 (F).
Mentions: To determine the possible involvement of other kinase pathways in DP signaling, we treated these cells with PGD2 in the absence and presence of highly selective inhibitors of PKC (BMIII), p38 (SB203580), and p44/42 MAPK (PD98059), and determined COX-2 mRNA expression by Northern blot analysis. We found that in BSM-2146 cells the inhibitors of all three kinases suppressed PGD2-mediated stimulation of COX-2 mRNA expression at varying degrees (Fig. 5 A), suggesting that in these cells DP signaling is mediated via activation of p38 and p44/42 MAPK and PKC pathways. In contrast, PGD2-mediated stimulation of COX-2 expression in NIH-3T3 cells was inhibited only by p38 MAPK inhibitor, SB203580 (Fig. 5 B), whereas in A549 cells only the PKC-specific inhibitor (BMIII) suppressed such stimulation (not depicted).

Bottom Line: These effects are abrogated by recombinant UG treatment.Here we report that DP signaling is mediated via p38 mitogen-activated protein kinase, p44/42 mitogen-activated protein kinase, and protein kinase C pathways in a cell type-specific manner leading to nuclear factor-kappaB activation stimulating COX-2 gene expression.Further, we found that recombinant UG blocks DP-mediated nuclear factor-kappaB activation and suppresses COX-2 gene expression.

View Article: PubMed Central - PubMed

Affiliation: Bldg. 10, Rm. 9S241, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.

ABSTRACT
Uteroglobin (UG) is an antiinflammatory protein secreted by the epithelial lining of all organs communicating with the external environment. We reported previously that UG-knockout mice manifest exaggerated inflammatory response to allergen, characterized by increased eotaxin and Th2 cytokine gene expression, and eosinophil infiltration in the lungs. In this study, we uncovered that the airway epithelia of these mice also express high levels of cyclooxygenase (COX)-2, a key enzyme for the production of proinflammatory lipid mediators, and the bronchoalveolar lavage fluid (BALF) contain elevated levels of prostaglandin D2. These effects are abrogated by recombinant UG treatment. Although it has been reported that prostaglandin D2 mediates allergic inflammation via its receptor, DP, neither the molecular mechanism(s) of DP signaling nor the mechanism by which UG suppresses DP-mediated inflammatory response are clearly understood. Here we report that DP signaling is mediated via p38 mitogen-activated protein kinase, p44/42 mitogen-activated protein kinase, and protein kinase C pathways in a cell type-specific manner leading to nuclear factor-kappaB activation stimulating COX-2 gene expression. Further, we found that recombinant UG blocks DP-mediated nuclear factor-kappaB activation and suppresses COX-2 gene expression. We propose that UG is an essential component of a novel innate homeostatic mechanism in the mammalian airways to repress allergen-induced inflammatory responses.

Show MeSH
Related in: MedlinePlus