Uteroglobin Represses Allergen-induced Inflammatory Response by Blocking PGD2 Receptor–mediated Functions

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–κB activation stimulating COX-2 gene expression. Further, we found that recombinant UG blocks DP-mediated nuclear factor–κB 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.

Lack of an Endogenous Anti-inflammatory Protein in Mice Enhances Colonization of B16F10 Melanoma Cells in the Lungs

“…We previously reported that the lungs of the UG-KO mice express genes that are known to mediate inflammation (17). In the present study, we found that the expression of several other genes related to inflammation (e.g.…”

“…UG-KO Mouse Lungs Express High Levels of S100A8 and S100A9-We previously reported that UG-KO mice are susceptible to pulmonary inflammation (17), and recently it has been demonstrated that RAGE and its ligands may constitute a FIGURE 2. Expression of S100A8 and S100A9 in WT and UG-KO mice and expression of RAGE in B16F10 cells.…”

“…It is constitutively expressed in the lungs of all mammals, and targeted disruption of the UG gene in mice (16) increases susceptibility to pulmonary inflammation (17). Moreover, we (18) and others (19) have previously demonstrated that overexpression of UG in cancer cells reverses their transformed phenotype and neoplastic potential.…”

The immune modulation of Clara cell-10 in human peripheral monocytes and dendritic cells

“…CC-10 appeared to have a high homology with rabbit uteroglobin, which has immunosuppressive, anti-inflammatory, anti-proteinase, and anti-phospholipase A2 properties (20)(21)(22)(23)(24). Therefore, CC-10 might play an important role in antiinflammatory response which is a critical factor for immune modulation in cancer prevention and treatment and CC-10 may used for a new marker indicating the severity of various inflammatory lung diseases (34).…”

“…CC-10 is the founding member of a growing superfamily of proteins called secretoglobin (Scgb) (19). Numerous studies have demonstrated that CC-10 is a multifunctional protein with anti-inflammatory (20) and immunomodulatory properties (21). It inhibits soluble phospholipase A2 activity (22), binds and perhaps sequesters hydrophobic ligands such as progesterone, retinols, polychlorinated biphenyls, phospholipids and prostaglandins.…”