Role of IL-18 in transplant biology

Abstract

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.

Phenotypic and Transcriptomic Lymphocytes Changes in Allograft Recipients After Intravenous Immunoglobulin Therapy in Kidney Transplant Recipients

“…Th17 responses especially Th1 responses (32), decreased significantly after IVIG high dose infusion. The main role of IL-18 is to crucially stimulate lymphocytes to produce the IFN-γ and regulate macrophages activity (32). However, in our study, serum levels decrease of IL-18 was not followed by a significant effect on serum levels of IFN-γ.…”

Identification of New Soluble Factors Correlated With the Development of Graft Failure After Haploidentical Hematopoietic Stem Cell Transplantation

“…Its function is normally regulated by the presence of the high-affinity molecule IL18BP. For this reason, Liu et al recently proposed to neutralize IL18 with IL18BP for the treatment of immune-mediated conditions, in which injury-associated cytokines are produced, including IFNg and CXCL10 (44). In support to the probable role of macrophages and endothelial damage in the development of GF, recently, IL18 has been also described as potential biomarker and therapeutic target of macrophage activation syndrome/HLH, which shares, as mentioned before, several important features with GF (45).…”

Protective Role of Kynurenine 3-Monooxygenase in Allograft Rejection and Tubular Injury in Kidney Transplantation

“…IL17 is associated with rejection ( 52 – 55 ). IL17 and IL6 are associated with rejection injury ( 56 – 58 ), while IL18 induces local cytokines and chemokine expression in the allograft ( 59 , 60 ). Quantitative PCR analysis showed that IL17 expression did not change in autografts but is increased 3.03-fold in the allografts.…”