Different regulation of interleukin-1 production and activity in monocytes and macrophages: innate memory as an endogenous mechanism of IL-1 inhibition.

Production and activity of IL-1 beta are kept under strict control in our body, because of its powerful inflammation-promoting capacity. Control of IL-1 beta production and activity allows IL-1 to exert its defensive activities without causing extensive tissue damage. Mononuclear phagocytes, in particular monocytes, are the major producers of IL-1 beta during inflammation, but they are also able to produce significant amounts of IL-1 inhibitors such as IL-1Ra and the soluble form of the decoy receptor IL-1R2, in an auto-regulatory feedback loop. Here, we investigated how innate immune memory could modulate production and activity of IL-1 beta by human primary monocytes and monocyte-derived tissue-like/deactivated macrophages in vitro. Cells were exposed to gram-negative (E. coli) and gram-positive (L. acidophilus) bacteria for 24 h, then allowed to rest, and then re-challenged with the same stimuli. The presence of biologically active IL-1 beta in cell supernatants was calculated as the ratio between free IL-1 beta (i.e., the cytokine that is not bound/inhibited by sIL-1R2) and its receptor antagonist IL-1Ra. As expected, we observed that the responsiveness of tissue-like/deactivated macrophages to bacterial stimuli was lower than that of monocytes. After resting and re-stimulation, a memory effect was evident for the production of inflammatory cytokines, whereas production of alarm signals (chemokines) was minimally affected. We observed a high variability in the innate memory response among individuals/donors. This could be explained by being the immune system tailored on previous infection experiences, so each subject respond differently based on its immunological history. This issue needs to be take into account especially when studying immune memory. Overall, innate memory appeared to limit the amount of active IL-1? produced by macrophages in response to a bacterial challenge, while enhancing the responsiveness of monocytes. The functional re-programming of mononuclear phagocytes through modulation of innate memory may provide innovative approaches in the management of inflammatory diseases, as well as in the design of new immunisation strategies.