Bronchial Epithelial Cell-Derived Prostaglandin E2 Dampens the Reactivity of Dendritic Cells

Abstract

Airway epithelial cells regulate immune reactivity of local dendritic cells (DCs), thus contributing to microenvironment homeostasis. In this study, we set out to identify factors that mediate this regulatory interaction. We show that tracheal epithelial cells secrete soluble factors that downregulate TNF-α and IL-12p40 secretion by bone marrow-derived DCs but upregulate IL-10 and arginase-1. Size exclusion chromatography identified small secreted molecules having high modulatory activity on DCs. We observed that airway tracheal epithelial cells constitutively release the lipid mediator PGE2. Blocking the synthesis of PGs within airway epithelial cells relieved DCs from inhibition. Cyclooxygenase-2 was found to be expressed in primary tracheal epithelial cell cultures in vitro and in vivo as shown by microdissection of epithelial cells followed by real-time PCR. Paralleling these findings we observed that DCs treated with an antagonist for E-prostanoid 4 receptor as well as DCs lacking E-prostanoid 4 receptor showed reduced inhibition by airway epithelial cells with respect to secretion of proinflammatory cytokines measured by ELISA. Furthermore, PGE2 mimicked the effects of epithelial cells on DCs. The results indicate that airway epithelial cell-derived PGE2 contributes to the modulation of DCs under homeostatic conditions.

The Key Role of IL-6–Arginase Cascade for Inducing Dendritic Cell–Dependent CD4+ T Cell Dysfunction in Tumor-Bearing Mice

“…In addition, IL-13 expression was not detected in the DC from the tumor-bearing mice (data not shown), indicating that these type-2 cytokines, with the exception of IL-6, are not involved in arginase-1 expression in this model. Moreover, previous studies (46,47) demonstrated that PGE 2 and IL-8 induced arginase expression in mouse DC or human tumor cells. We examined mRNA expression levels of Cox-2, Ptges (PGE 2 -related factors), and KC (murine IL-8 homolog) in the tumor cells used in the present experiments.…”

Reciprocal crosstalk between dendritic cells and natural killer cells under the effects of PGE2 in immunity and immunopathology

“…PGE2 produced by airway epithelial cells induces the differentiation of DCs with an anti-inflammatory phenotype characterized by reduced secretion of TNF-alpha and increased secretion of IL-10. 97 Airway epithelial cell-derived PGE2 reduces the pro-inflammatory activity of DCs and limits their activity through an EP4 receptor-dependent mechanism. PGE2 has well-established protective and beneficial effects in asthma.…”

Bronchial Epithelial Cells Induce Alternatively Activated Dendritic Cells Dependent on Glucocorticoid Receptor Signaling

“…Isolation and culture of murine tracheal epithelial cells (mTrECs) were performed as previously described (2). Briefly, 8-10-wk-old female C57BL/6 mice (Charles River Laboratories, Sulzfeld, Germany) were sacrificed by CO 2 asphyxia, and tracheae were dissected and digested with Pronase E and DNAseI overnight at 4˚C.…”

“…Recently, we and others (2,11,12) demonstrated that respiratory epithelial cells are able to suppress proinflammatory cytokine secretion of LPS-stimulated DCs through the constitutive production of PGE 2 , TSLP, macrophage-derived chemokine, or thymus-and activation-regulated chemokine. Other soluble, epithelial cell-derived factors with immune-modulatory potential have been described (1,13,14).…”

“…To avoid detrimental inflammatory processes under homeostatic conditions, a specific respiratory microenvironment exists that controls and limits inflammatory reactivity (1)(2)(3)(4)(5). Thus, stromal nonprofessional immune cells regulate organ-specific immunity (6).…”