Down-modulation of mycobacterial-induced IL-1β production in human mononuclear cells by IL-4

Tuberculosis is characterized by a cellular immune response mediated by various cytokines, including IL-1β released by stimulated mononuclear cells. It is now well established that IL-1β plays an important role in local and systemic inflammatory response in tuberculosis. Here we have demonstrated, for the first time, that addition of IL-4 to human mononuclear cells obtained from 11 healthy bacille Calmette-Guerin (BCG)-vaccinated donors reduced BCG-induced production of IL-1β by 91.46 ± 2.2%. This inhibitory effect was found highly significant (P < 0.001) and was dose-dependent. The effect of IL-4 on the secretion of IL-1β was specific, since a complete reversion was obtained with a neutralizing MoAb to human IL-4. In addition, this inhibitory effect was not attributed to a cytotoxic effect, since trypan blue exclusion studies indicated no loss of cell viability in response to IL-4. Interestingly, the induction of IL-3 was regulated by IL-4, at least in part, by a direct mechanism mediated through the 130 extracellular domain of the IL-4 receptor, as demonstrated by incubation of the mononuclear cells with the neutralizing anti-IL-4 receptor MoAb. Finally, a significant down-regulation of IL-1β secretion was observed in hsp70-stimulated mononuclear cells cultured with IL-4. Further experimental work is needed to establish the relevance of IL-4 in human mycobacterial infection in vivo. However, an understanding of the mechanisms that control IL-1β secretion in hman mycobacterial infections is essential to understand the pathogenesis of tuberculosis.