A New Concept of the Old Inhibitor NSC 74859 in Alleviating Cardiac Allograft Rejection and Extending Allograft Survival in Mice

BACKGROUND: STAT1/4 has been suggested to be involved in cardiac allograft rejection. However, no direct evidence regarding STAT3 has been established in cardiac allograft rejection. Here, we hypothesized that inhibition of STAT3 attenuates cardiac allograft rejection. MATERIAL/METHODS: To test our hypothesis, homotopic mouse heart transplantation was carried out in syngeneic C57BL/6 to C57BL/6 strain mice with or without oral gavage with NSC 74859, an inhibitor of STAT3. The immune response was investigated using real-time PCR for CD4 and CD8 surface makers of T cells and CD14 of monocytes and cytokines, including IL-2, IL-15, and IL-6 of allografts at 3, 6, and 9 days after transplantation. Prognosis was also evaluated. RESULTS: We found that allografts with oral gavage of NSC 74859 whose CD4, CD8 T, and CD14 monocytes were significantly lower than that of allograft without oral gavage of NSC 74859, and the same was true for the expression of IL-2, IL-15, and IL-6. Immunohistochemical analysis of grafts showed reduced infiltration of monocytes/macrophages into the graft myocardium. Survival was also markedly extended in the NSC 74859 group. CONCLUSIONS: Inhibition of IL-6/STAT3 using NSC 74859 was shown to remarkably alleviate cardiac allograft rejection in mice, indicating that the target against IL-6/STAT3 pathway might be clinically used as an alternative therapy for cardiac allograft rejection.