SLPI Inhibits ATP-Mediated Maturation of IL-1beta in Human Monocytic Leukocytes: A Novel Function of an Old Player

Abstract

Interleukin-1beta (IL-1beta) is a potent, pro-inflammatory cytokine of the innate immune system that plays an essential role in host defense against infection. However, elevated circulating levels of IL-1beta can cause life-threatening systemic inflammation. Hence, mechanisms controlling IL-1beta maturation and release are of outstanding clinical interest. Secretory leukocyte protease inhibitor (SLPI), in addition to its well-described anti-protease function, controls the expression of several pro-inflammatory cytokines on the transcriptional level. In the present study, we tested the potential involvement of SLPI in the control of ATP-induced, inflammasome-dependent IL-1beta maturation and release. We demonstrated that SLPI dose-dependently inhibits the ATP-mediated inflammasome activation and IL-1beta release in human monocytic cells, without affecting the induction of pro-IL-1beta mRNA by LPS. In contrast, the ATP-independent IL-1beta release induced by the pore forming bacterial toxin nigericin is not impaired, and SLPI does not directly modulate the ion channel function of the human P2X7 receptor heterologously expressed in Xenopus laevis oocytes. In human monocytic U937 cells, however, SLPI efficiently inhibits ATP-induced ion-currents. Using specific inhibitors and siRNA, we demonstrate that SLPI activates the calcium-independent phospholipase A2beta (iPLA2beta) and leads to the release of a low molecular mass factor that mediates the inhibition of IL-1beta release. Signaling involves nicotinic acetylcholine receptor subunits alpha7, alpha9, alpha10, and Src kinase activation and results in an inhibition of ATP-induced caspase-1 activation. In conclusion, we propose a novel anti-inflammatory mechanism induced by SLPI, which inhibits the ATP-dependent maturation and secretion of IL-1beta. This novel signaling pathway might lead to development of therapies that are urgently needed for the prevention and treatment of systemic inflammation.