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

Abstract

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-γ 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-1α. Recombinant IL-1 directly augments IFN-γ 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-γ, 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.

High-mobility group box 1 promotes early acute allograft rejection by enhancing IL-6-dependent Th17 alloreactive response

“…3,28 Activated neutrophils have been suggested to have significant implications in the pathogenesis of allograft rejection. 32 Combining our observations together with others, 31 we propose that Th17 alloreactive response provides a rapid influx of neutrophils into the grafts, which then mediate early graft damage when the development of IFN-g-producing T cells is still at the early stage. However, once these IFN-g-producing T cells are dominant at the late stage of rejection, resulting in the influx of monocyte/macrophages into the grafts, the actions of IL-17-producing T cells are then receded to a relatively low level.…”

“…Interestingly, HMGB1 functions by inducing IL-1b secretion from monocytes through TLR4 and CD14. 31 Our data indicate that HMGB1 also enhances Th17 alloreactive response by inducing IL-6 production from DCs. It has been shown that IL-17 acts as a potent proinflammatory cytokine to induce tissue damage at least in part through neutrophil recruitment.…”

IL-36 receptor is expressed by human blood and intestinal T lymphocytes and is dose–dependently activated via IL-36β and induces CD4+ lymphocyte proliferation

“…producing, CD4+ Th cells [18] and IL-17/Th memory cell populations [19]. Due to measuring proliferation after only 48h, our studies show that there is a rapid effect of IL-36β which cannot be due merely to increased survival as has been shown in some other studies mentioned above.…”

Lung Diseases - Selected State of the Art Reviews

“…These mediators include some of the cytokines that are important in T cell differentiation such as TGFβ (Basile et al 2001). A recent study demonstrated that factors released by human endothelial cells as a consequence of ischemia-reperfusion injury could enhance the production of both IL-17 and IFNγ by CD4 + T cells (Rao, Tracey, and Pober 2007). These findings indicate that perioperative factors might result in increased Th17 activity within the graft.…”