ClyA enhances LPS-induced IL-1ß secretion in human macrophages through TLR4 and NLRP3 signaling.

ABSTRACT

Lipopolysaccharide (LPS) plays an important role in tumor suppression by activating macrophages. After macrophages activation, a trail of cytokines was secreted, including IL-1ß. Previous studies reported that the anti-tumor function of IL-1ß is concentration-dependent, and increasing the level of IL-1ß will enhance its anti-tumor effect. Cytolysin A (ClyA), a member of the protein family called pore-forming toxins (PFTs), is secreted by Gram-negative bacteria, which has a potential role in enhancing the secretion of IL-1ß. In this study, the function of Cytolysin A was evaluated by investigating its ability to induce innate immune responses in macrophages and the signaling pathway(s) involved in LPS-induced production of IL-1ß. The production of IL-1ß was highly enhanced when the macrophages were treated with LPS and ClyA together. The production of IL-1ß was regulated by TLR4-MyD88-IL-1ß pathway and NLRP3-ASC-Caspase1-IL1ß pathway. By treating the colon cancer cell line CT26 with the conditioned medium, the proliferation of CT26 cells was inhibited and the apoptosis of CT26 cells was increased. In conclusion, this study indicated that ClyA enhances the production of IL-1ß induced by LPS in human macrophages. The proliferation of CT26 cells was inhibited and the apoptosis was increased when being treated with the macrophage-conditioned media, which provides a feasible treatment for colon tumor.