X.Z. and O.B. contributed equally to this work.
Critical Role of Proinflammatory Cytokine IL-6 in Allograft Rejection and Tolerance
Article first published online: 12 OCT 2011
©Copyright 2011 The American Society of Transplantation and the American Society of Transplant Surgeons
American Journal of Transplantation
Volume 12, Issue 1, pages 90–101, January 2012
How to Cite
Zhao, X., Boenisch, O., Yeung, M., Mfarrej, B., Yang, S., Turka, L. A., Sayegh, M. H., Iacomini, J. and Yuan, X. (2012), Critical Role of Proinflammatory Cytokine IL-6 in Allograft Rejection and Tolerance. American Journal of Transplantation, 12: 90–101. doi: 10.1111/j.1600-6143.2011.03770.x
- Issue published online: 13 JAN 2012
- Article first published online: 12 OCT 2011
- Received 02 December 2010, revised 05 August 2011 and accepted for publication 19 August 2011
- Allograft tolerance;
- costimulation blockade;
The proinflammatory cytokine IL-6 plays an important role in controlling T-cell differentiation, especially the development of Th17 and regulatory T cells. To determine the function of IL-6 in regulating allograft rejection and tolerance, BALB/c cardiac grafts were transplanted into wild-type or IL-6-deficient C57BL/6 mice. We observed that production of IL-6 and IFN-γ was upregulated during allograft rejection in untreated wild-type mice. In IL-6-deficient mice, IFN-γ production was greater than that observed in wild-type controls, suggesting that IL-6 production affects Th1/Th2 balance during allograft rejection. CD28-B7 blockade by CTLA4-Ig inhibited IFN-γ production in C57BL/6 recipients, but had no effect on the production of IL-6. Although wild-type C57BL/6 recipients treated with CTLA4-Ig rejected fully MHC-mismatched BALB/c heart transplants, treatment of IL-6-deficient mice with CTLA4-Ig resulted in graft acceptance. Allograft acceptance appeared to result from the combined effect of costimulatory molecule blockade and IL-6-deficiency, which limited the differentiation of effector cells and promoted the migration of regulatory T cells into the grafts. These data suggest that the blockade of IL-6, or its signaling pathway, when combined with strategies that inhibit Th1 responses, has a synergistic effect on the promotion of allograft acceptance. Thus, targeting the effects of IL-6 production may represent an important part of costimulation blockade-based strategies to promote allograft acceptance and tolerance.