Protons trigger IL-1beta production in human monocytes.

GHIBAUDI N; RODRIGUEZ RODRIGUEZ C; CABRINI M; REMES LENICOV, F; GABELLONI ML,; TREVANI AS; GEFFNER JR; JANCIC C

Congreso; First French-Argentine Immunology Congress; 2010

Sociedad Francesa de Inmunología y Sociedad Argentina de Inmunología

Interstitial acidification (pH5.5-7.0) is a common feature associated with the course of many inflammatory reactions in peripheral tissues. Autoimmune diseases such as rheumatoid arthritis and asthma, as well as the growth of solid tumors are also associated with the development of acidic microenvironments. We have previously reported that extracellular acidosis induces the activation of neutrophils and dendritic cells, supporting the idea that low pH can be recognized by immune cells as a danger signal favouring the initiation of immune responses. Here, we studied the effect of low extracellular pH (pHe) on monocyte function by incubating cells with an isotonic hydrogen chloride solution to allow an pHe of 6.5. We analyzed phenotype and cytokine secretion, in particular IL-1beta production which was assessed by ELISA, flow cytometry and confocal microscopy. We observed that low pHe did not induce changes in the expression of CD40, CD86 and HLA-DR. However, cells exposed to pH 6.5 secreted higher levels of IL-1beta compared with controls (pH 6.5: 174pg/ml±42 vs. pH 7.3: 82pg/ml±19; n=25; p<0.05). Furthermore, by intracellular staining we detected higher expression of IL-1beta in monocytes exposed to pH 6.5 (p<0.05; n=3) (by flow cytometry and confocal microscopy). The increase in IL-1beta production induced by extracellular acidosis was found to be associated with a fall in intracellular pH, as assessed by flow cytometry: pH 6.5-treated-cells: 6.8±0.07 vs. resting cells: 7.18±0.03; n=10, p<0.0005). Moreover, we also found that the treatment of monocytes with cycloheximide prevented the rise in IL-1beta levels in response to pH 6.5 (p<0.05; n=3), supporting the idea that stimulation of IL-1beta production is related to an increased synthesis of the IL-1beta precursor: pro-IL-1beta. Our results suggest that stimulation of IL-1beta production in human monocytes appears to represent a novel mechanism through which extracellular acidosis contributes to the development of inflammatory processes.