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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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UG inhibits COX-2 expression induced by allergens in vivo and by PGD2 in vitro. (A) Northern blot analysis of COX-2 mRNA expression in the lungs of control WT (lane 1) and control UG-KO (lane 2), OVA-sensitized and -challenged WT (lane 3), OVA-sensitized and -challenged UG-KO (lane 4), and OVA-sensitized and rUG-treated before OVA challenge of UG-KO (lane 5) mice. (B) COX-2 immunofluorescence in representative control WT (frame 1) and control UG-KO (frame 2) mice; WT mouse sensitized and challenged with OVA (frame 3); UG-KO mouse sensitized and challenged with OVA (frame 4); UG-KO mouse sensitized and treated with rUG before OVA challenge (frame 5). b, bronchiole. Magnification, ×400. Time-course of PGD2-induced COX-2 mRNA expression in BSM-2146 (C) and NIH-3T3 (D) cells. Dose–response of PGD2-induced stimulation of COX-2 mRNA expression in BSM-2146 (E) and NIH-3T3 (F) cells. Western blot analysis demonstrating PGD2-induced COX-2 protein expression in BSM-2146 (G) and NIH-3T3 cells (H).
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fig2: UG inhibits COX-2 expression induced by allergens in vivo and by PGD2 in vitro. (A) Northern blot analysis of COX-2 mRNA expression in the lungs of control WT (lane 1) and control UG-KO (lane 2), OVA-sensitized and -challenged WT (lane 3), OVA-sensitized and -challenged UG-KO (lane 4), and OVA-sensitized and rUG-treated before OVA challenge of UG-KO (lane 5) mice. (B) COX-2 immunofluorescence in representative control WT (frame 1) and control UG-KO (frame 2) mice; WT mouse sensitized and challenged with OVA (frame 3); UG-KO mouse sensitized and challenged with OVA (frame 4); UG-KO mouse sensitized and treated with rUG before OVA challenge (frame 5). b, bronchiole. Magnification, ×400. Time-course of PGD2-induced COX-2 mRNA expression in BSM-2146 (C) and NIH-3T3 (D) cells. Dose–response of PGD2-induced stimulation of COX-2 mRNA expression in BSM-2146 (E) and NIH-3T3 (F) cells. Western blot analysis demonstrating PGD2-induced COX-2 protein expression in BSM-2146 (G) and NIH-3T3 cells (H).

Mentions: COX-2 gene expression in the lungs of allergic asthma patients is markedly elevated (17). Since COX-2 is an agonist-inducible enzyme that catalyzes the production of proinflammatory lipid mediators, we first analyzed COX-2 gene expression in the lungs of nonsensitized and unchallenged UG-KO and WT littermates. The results show that a low level of COX-2 mRNA expression is detectable in the lungs of the WT littermates (Fig. 2 A, lane 1) and in those of the UG-KO (Fig. 2 A, lane 2) mice. In contrast, although COX-2 mRNA expression in the lungs of OVA-sensitized and challenged WT mice increased slightly (Fig. 2 A, lane 3), the expression levels in UG-KO mice were markedly elevated (Fig. 2 A, lane 4). Most importantly, treatment of OVA-sensitized UG-KO mice with rUG before OVA challenge showed an appreciable inhibition of COX-2 mRNA expression (Fig. 2 A, lane 5). We also found that compared with the intensity of COX-2 immunofluorescence in the bronchioles of control WT and UG-KO mice (Fig. 2 B, frames 1 and 2) immunofluorescence of the OVA-sensitized and challenged WT mice were only slightly elevated (Fig. 2 B, frame 3). However, COX-2 immunofluorescence was strikingly intense in the bronchioles of OVA-sensitized and challenged UG-KO mice (Fig. 2 B, frame 4). Significantly, the intensity of COX-2 immunofluorescence in OVA-sensitized UG-KO mice, treated with rUG before OVA challenge was markedly less intense (Fig. 2 B, frame 5), suggesting that UG suppresses allergen-induced stimulation of COX-2 gene expression in the lungs.


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)

UG inhibits COX-2 expression induced by allergens in vivo and by PGD2 in vitro. (A) Northern blot analysis of COX-2 mRNA expression in the lungs of control WT (lane 1) and control UG-KO (lane 2), OVA-sensitized and -challenged WT (lane 3), OVA-sensitized and -challenged UG-KO (lane 4), and OVA-sensitized and rUG-treated before OVA challenge of UG-KO (lane 5) mice. (B) COX-2 immunofluorescence in representative control WT (frame 1) and control UG-KO (frame 2) mice; WT mouse sensitized and challenged with OVA (frame 3); UG-KO mouse sensitized and challenged with OVA (frame 4); UG-KO mouse sensitized and treated with rUG before OVA challenge (frame 5). b, bronchiole. Magnification, ×400. Time-course of PGD2-induced COX-2 mRNA expression in BSM-2146 (C) and NIH-3T3 (D) cells. Dose–response of PGD2-induced stimulation of COX-2 mRNA expression in BSM-2146 (E) and NIH-3T3 (F) cells. Western blot analysis demonstrating PGD2-induced COX-2 protein expression in BSM-2146 (G) and NIH-3T3 cells (H).
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fig2: UG inhibits COX-2 expression induced by allergens in vivo and by PGD2 in vitro. (A) Northern blot analysis of COX-2 mRNA expression in the lungs of control WT (lane 1) and control UG-KO (lane 2), OVA-sensitized and -challenged WT (lane 3), OVA-sensitized and -challenged UG-KO (lane 4), and OVA-sensitized and rUG-treated before OVA challenge of UG-KO (lane 5) mice. (B) COX-2 immunofluorescence in representative control WT (frame 1) and control UG-KO (frame 2) mice; WT mouse sensitized and challenged with OVA (frame 3); UG-KO mouse sensitized and challenged with OVA (frame 4); UG-KO mouse sensitized and treated with rUG before OVA challenge (frame 5). b, bronchiole. Magnification, ×400. Time-course of PGD2-induced COX-2 mRNA expression in BSM-2146 (C) and NIH-3T3 (D) cells. Dose–response of PGD2-induced stimulation of COX-2 mRNA expression in BSM-2146 (E) and NIH-3T3 (F) cells. Western blot analysis demonstrating PGD2-induced COX-2 protein expression in BSM-2146 (G) and NIH-3T3 cells (H).
Mentions: COX-2 gene expression in the lungs of allergic asthma patients is markedly elevated (17). Since COX-2 is an agonist-inducible enzyme that catalyzes the production of proinflammatory lipid mediators, we first analyzed COX-2 gene expression in the lungs of nonsensitized and unchallenged UG-KO and WT littermates. The results show that a low level of COX-2 mRNA expression is detectable in the lungs of the WT littermates (Fig. 2 A, lane 1) and in those of the UG-KO (Fig. 2 A, lane 2) mice. In contrast, although COX-2 mRNA expression in the lungs of OVA-sensitized and challenged WT mice increased slightly (Fig. 2 A, lane 3), the expression levels in UG-KO mice were markedly elevated (Fig. 2 A, lane 4). Most importantly, treatment of OVA-sensitized UG-KO mice with rUG before OVA challenge showed an appreciable inhibition of COX-2 mRNA expression (Fig. 2 A, lane 5). We also found that compared with the intensity of COX-2 immunofluorescence in the bronchioles of control WT and UG-KO mice (Fig. 2 B, frames 1 and 2) immunofluorescence of the OVA-sensitized and challenged WT mice were only slightly elevated (Fig. 2 B, frame 3). However, COX-2 immunofluorescence was strikingly intense in the bronchioles of OVA-sensitized and challenged UG-KO mice (Fig. 2 B, frame 4). Significantly, the intensity of COX-2 immunofluorescence in OVA-sensitized UG-KO mice, treated with rUG before OVA challenge was markedly less intense (Fig. 2 B, frame 5), suggesting that UG suppresses allergen-induced stimulation of COX-2 gene expression in the lungs.

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