HOMOLOGOUS DESENSITIZATION TO PROSTAGLANDIN E2 IN HUMAN MONOCYTES IS MEDIATED BY INDUCTION OF PHOSPHODIESTERASE 4B EXPRESSION

V. RAMIREZ; G. CABRERIZO; F. DI DIEGO GARCÍA; A. PALETTA; A. CEBALLOS; F. REMES LENICOV

San Luis

Congreso; LXXI REUNIÓN CIENTÍFICA ANUAL DE LA SOCIEDAD ARGENTINA DE INMUNOLOGÍA; 2023

SOCIEDAD ARGENTINA DE INMUNOLOGÍA

Prostaglandin E2 (PGE2) is a well-known lipid mediator with inflammatory and anti-inflammatory properties. While PGE2 is recognized for inhibiting LPS-induced activation of monocytes, our previous work has demonstrated that long-term exposure of monocytes to PGE2 increased their ability to produce LPS-induced TNF. We found that increased TNF production was explained by disruption of the negative feedback elicited by LPS-induced endogenous PGE2. This PGE2-mediated abrogation of PGE2 signaling is known as homologous desensitization.In cell line models, PGE2 has been shown to trigger desensitization either by downregulating specific receptors EP2 and EP4, or by inducing phosphodiesterases (PDE), which terminate PGE2 signal by hydrolyzing second messenger cyclic AMP. In this work we aim to study the mechanism leading to homologous desensitization to PGE2 in human monocytes.Monocytes were purified from peripheral blood and desensitized by culturing for 15 hours in the presence of low concentrations of PGE2 (10-8 M). Control monocytes were cultured for 15 hours without treatment. Spontaneous apoptosis was measured by annexin V staining and was found equivalent in both conditions. To test desensitization, cultured monocytes were stimulated with LPS (25 ng/ml), in the presence, or not, of a second pulse of PGE2 (10-7 M). Then, TNF was evaluated by intracytoplasmic staining flow cytometry.As expected, LPS-induced TNF expression in monocytes pre-treated with PGE2 for 15 hours was not inhibited by a second pulse of PGE2 (n=7, p