Prostaglandin E2 Inhibits IFN-α Secretion and Th1 Costimulation by Human Plasmacytoid Dendritic Cells via E-Prostanoid 2 and E-Prostanoid 4 Receptor Engagement

Abstract

Plasmacytoid dendritic cell (PDC)-derived IFN-α plays a central role in antiviral defense and in Th1-driven autoimmune diseases, such as systemic lupus erythematosus (SLE). In the current study, we explored how PGE2 effects the phenotype of PDCs from healthy and SLE subjects. Although PGE2 is considered to mediate mainly proinflammatory effects, we show that PGE2 and PG analogs potently inhibit secretion of IFN-α by TLR-activated PDCs. This effect is mainly mediated by PG receptors E-prostanoid 2 and E-prostanoid 4 and involves inhibition of IFN regulatory factor 7 expression. Of note, profound IFN-α inhibition by PGE2 is also seen in PDCs from SLE subjects, independent of age, disease activity, and therapy. We show that TLR9-activated PDCs treated with PGE2 exhibit DC2-like characteristics with enhanced expression of CD86 and CD62L, and decreased expression of CD80 and MHC class I. Consequently, PGE2-treated PDCs suppress secretion of Th1 cytokines by T cells while increasing the secretion of Th2 cytokines. Prevention of CpG-induced CD62L downregulation by PGE2 suggests that it may induce the retreat of PDCs from inflamed tissues. Our data on the effects of PGE2 on PDCs may explain occasional reports about the induction of SLE-like symptoms by cyclooxygenase inhibitors as well as improvement of such symptoms by treatment with PG analogs. In conclusion, our data suggest that PGE2 and certain PG analogs, some of which are already in clinical use, should be evaluated as a novel and inexpensive treatment approach for patients with SLE and other IFN-α–dependent, Th1-driven autoimmune diseases.

Loss of the Type I Interferon Pathway Increases Vulnerability of Mice to Genital Herpes Simplex Virus 2 Infection

“…We postulated type I IFNs constituted a critical component of the innate immune system that normally reduces the likelihood of HSV-2 transmission in an otherwise healthy mouse. Consistent with this hypothesis, prostaglandin pretreatment suppresses local HSV-2 antibody titers and inhibits IFN-␣ pro-duction by pDCs and Th1 development in mice and humans, respectively (15,29).…”

“…WT mice are highly susceptible to vaginal challenge with HSV-2 when pretreated with medoxyprogesterone formulations such as DP (29). Progesterone suppresses IFN-␣ production by pDCs and Th1 development (15,29), which are key cellular components in resistance to HSV-2 replication. Thus, we sought to determine if the resistance of untreated mice to HSV-2 was dependent on the type I interferon response.…”

Dendritic cells from human mesenteric lymph nodes in inflammatory and non‐inflammatory bowel diseases: subsets and function of plasmacytoid dendritic cells

“…53 Lipid mediators such as prostaglandin E 2 have also been shown to inhibit the IFN-a secretion by human pDC. 54 In summary, MLN pDC are rather immature and non-activated, similar in phenotype to control PB pDC. Functional analyses revealed the development of both IL-10-producing and IFN-c-producing T effector cells by pDC from MLN but not from PB.…”

Plasmacytoid Dendritic Cells Alter the Antitumor Activity of CpG-Oligodeoxynucleotides in a Mouse Model of Lung Carcinoma

“…The presence of PGE 2 (42) and the production of IgE (43) can counter pDC activation via the inhibition of IFN type I. Because lung cancer is a Th2-like pathology during which PGE 2 and IgE are highly produced (44) (data not shown), we could speculate that the interference with IFN type I derived from pDCs could render these cells more prone to induce a tolerogenic environment.…”