Interleukin-18 Production Following Murine Cardiac Transplantation: Correlation with Histologic Rejection and the Induction of IFN-γ

Abstract

Interleukin-18 (IL-18) and IL-12 have been shown to play an important role in the induction of interferon-gamma (IFN-gamma). IFN-gamma induces the proliferation of T cells and natural killer (NK) cells and augments the Th1 immune cascade. The role of IL-18 and IL-12 in the induction of IFN-gamma following allogeneic heart transplantation has not been described. We sought to characterize the IL-12 and IL-18 response to murine allogeneic heart transplantation, particularly with respect to IFN-gamma production and histologic transplant rejection. Forty-eight heterotopic heart transplants were performed in two groups of mice: syngeneic C3H/HeN to C3H/HeN mice and allogeneic BALB/C to C3H/HeN mice. Transplants were followed out to 2, 6, 10, and 14 days. Six transplants were performed in each group. Serum and splenic samples were used to evaluate the cytokine response by ELISA. Explanted heart tissue was processed for evidence of histologic rejection, and RT-PCR was performed to evaluate the IL-12, IL-18, and IFN-gamma signal qualitatively. Analysis of variance (ANOVA), Fisher's projected least significant difference (PLSD) was used for statistical analysis. Transplant rejection occurred in the allogeneic group histologically by day 6 and clinically by day 10. Serum IFN-gamma levels rose significantly by day 6 in the allogeneic group and then continued to rise in the splenocyte cultures. Serum IL-18 also rose significantly in the allogeneic group at day 6 compared with syngeneic group. RT-PCR revealed that the allogeneic tissue contained an increased signal for IL-12, IL-18, and IFN-gamma beginning at day 6 and peaking at day 10 after transplant. Beginning 6 days after transplantation, IL-12 and IL-18 appear to play a significant role in the induction of IFN-gamma in allogeneic heart transplants.

Unique Regulation Profile of Prostaglandin E1on Adhesion Molecule Expression and Cytokine Production in Human Peripheral Blood Mononuclear Cells

“…IL-18 has been considered a mediator of inflammatory disease such as allorejection after organ transplantation, rheumatoid arthritis, or hepatitis (Saha et al, 1999;Affleck et al, 2001;Yumoto et al, 2002). Using a mouse model, recent studies reported that PGE 1 reduced ischemia-reperfusion injury following lung transplantation (de Perrot et al, 2001), collagen induced arthritis (Moriuchi-Murakami et al, 2000), and LPS-induced liver injury (Mokuno et al, 1999).…”

Interleukin 18 (IL-18) upregulation in acute rejection of kidney allograft

“…On the other hand, IL-18 seems to play a positive role in the resolution of the posttransplant lymphoproliferative disorder since the serum level of IL-18 increases significantly during the regression and follow-up in those patients with long-term operational tolerance [19]. In a murine model of cardiac transplantation, IL-18 production correlated with histologic pattern of rejection and the induction of IFN-␥ [20], however, the clinical data focussed on IL-18 production in organ transplantation remain insufficient. Therefore, the aim of our study was to localize IL-18 producing cells in renal parenchyma of kidney allograft recipients, measure IL-18 serum levels in early postoperative period following kidney transplantation, and assess the IL-18 gene expression in a tissue culture model of renal epithelial cells.…”

Suppressive Effects of Interleukin-18 on Liver Function in Rat Liver Allografts

“…Serum levels of IL-18 have been found to be elevated in patients with postoperative sepsis [20], chronic liver disease [21][22][23][24][25], and acute coronary syndromes [26]. In a murine model of cardiac transplantation, IL-18 production was correlated with a histologic rejection pattern and with induction of IFN-g [27]. Although in a previous study, levels of IL-18 mRNA in liver allografts (ACI to Lewis) peaked the d 5 after transplantation whereas liver isografts (Lewis to Lewis) had no such peaks [28], the effect of inhibition of IL-18 mRNA on acute cellular rejection (ACR) remains unclear.…”