Role of IL-18 in transplant biology

Since pro-inflammatory cytokine IL-18 and its receptor (IL-18R) are closely involved in regulating both adaptive and innate immune responses, it is conceivable that they might play an important role in organ transplantation.IL-18 can stimulate lymphocytes to produce the IFN-␥ and regulate macrophage activity, thereby increasing the expression of proinflammatory cytokines including IL-1␤, IL-6, CCL4 (macrophage inflammatory protein-1 ␤), CXCL2 (macrophage inflammatory protein-2), and CCL2 (monocyte chemotactic protein-1).Nevertheless, the IL-18 signaling pathway and its underlying mechanisms remain obscure in transplant biology.This review is to summarize recent advances in our knowledge about the IL-18 signaling pathway and to analyze their functions in transplant-related biology.It was found that IL-18/IL-18R signaling pathway contributed to vascular transplantation, ischemmia/reperfusion, acute kidney injury, and acute rejection of kidney/liver/heart transplantation.IL-18 was a potential CYP3A expression modulator and was capable of affecting tacrolimus pharmacokinetics.Neutralizing IL-18 by its inhibitor IL-18 binding protein could efficiently suppress the production of injury-associated cytokines such as IL-6, TNF-␣, IFN-␥, CXCL10 (IFN-␥-inducible protein10), and CX 3 CL1 (fractalkine) and improve allograft function.Blockade of IL-18 signaling could regulate cardiomyocyte apoptosis and inhibit Th17 cells differentiation.Alteration of IL-18 levels was suggested as a biomarker for predicting ongoing allograft outcome.All these activities could deepen our understanding of immunobiological role of IL-18 and its receptor in the field of organ transplantation.Intervention of IL-18 signaling pathway might be utilized as a therapeutic strategy in clinic.