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IL-1 and IL-1β Are Endogenous Mediators Linking Cell Injury to the Adaptive Alloimmune Response¹

Deepak A. Rao^*, Kevin J. Tracey and Jordan S. Pober^2,*,,

^* Department of Immunobiology, Department of Pathology, and Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510; and Laboratories of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY 11030

Preoperative or perioperative ischemic injury of allografts predisposes to graft arteriosclerosis, the major cause of late graft failure. We hypothesize that injured tissues release mediators that increase the production of pathogenic cytokines by alloreactive T cells. We find that freeze-thaw lysates of human endothelial cells (EC) increase both IFN- and IL-17 production by human CD4⁺ T cells activated by HLA-DR⁺ allogeneic EC. Immunoadsorption of high-mobility group box 1 protein (HMGB1) reduces this activity in the lysates by about one-third, and recombinant HMGB1 increases T cell cytokine production. HMGB1 acts by inducing IL-1β secretion from contaminating monocytes via TLR4 and CD14. Upon removal of contaminating monocytes, the remaining stimulatory activity of EC lysates is largely attributable to IL-1. Recombinant IL-1 directly augments IFN- and IL-17 production by activated memory CD4⁺ T cells, which express IL-1R1. Furthermore, IL-1 increases the frequency of alloreactive memory CD4⁺ T cells that produce IL-17, but not those that produce IFN-, in secondary cultures. Our results suggest that IL-1, released by injured EC or by HMGB1-stimulated monocytes, is a key link between injury and enhanced alloimmunity, offering a new therapeutic target for preventing late graft failure.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health National Heart, Lung, and Blood Institute (to J.S.P.) and National Institute of General Medical Sciences to (K.J.T.). D.A.R. is supported by the Medical Scientist Training Program.

² Address correspondence and reprint requests to Dr. Jordan S. Pober, Yale University School of Medicine, Amistad Building, 10 Amistad Street, New Haven, CT 06509. E-mail address: jordan.pober{at}yale.edu

³ Abbreviations used in this paper: EC, endothelial cell; AGER, advanced glycosylation end product-specific receptor; HMGB1, high-mobility group box 1; ICS, intracellular cytokine staining.