Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions.
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.
Mandal
Asim K
AK
Bldg. 10, Rm. 9S241, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Zhang
Zhongjian
Z
Ray
Rabindranath
R
Choi
Moonsuk S
MS
Chowdhury
Bhabadeb
B
Pattabiraman
Nagarajan
N
Mukherjee
Anil B
AB
D016475:3T3 Cells; D000485:Allergens; D000818:Animals; D001980:Bronchi / Q000502:physiology; D002460:Cell Line; D051546:Cyclooxygenase 2; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D007527:Isoenzymes / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D009130:Muscle, Smooth / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D011650:Pulmonary Alveoli / Q000502:physiology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000502:physiology*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014598:Uteroglobin / Q000494:pharmacology*
D000485:Allergens; D007527:Isoenzymes; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D011994:Recombinant Proteins; D014598:Uteroglobin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C036293:prostaglandin D2 receptor