Interleukin-33 Drives a Proinflammatory Endothelial Activation That Selectively Targets Nonquiescent Cells.
Pollheimer, Jurgen; Bodin, Johanna; Sundnes, Olav; Edelmann, Reidunn J.; Skanland, Sigrid S.; Sponheim, Jon; Brox, Mari Johanna; Sundlisaeter, Eirik; Loos, Tamara; Vatn, Morten; Kasprzycka, Monika; Wang, Junbai; Kuchler, Axel M.; Tasken, Kjetil; Haraldsen, Guttorm; Hol, Johanna
Arteriosclerosis, Thrombosis & Vascular Biology.
33(2):e47-e55, February 2013.
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Objective-: Interleukin (IL)-33 is a nuclear protein that is released from stressed or damaged cells to act as an alarmin. We investigated the effects of IL-33 on endothelial cells, using the prototype IL-1 family member, IL-1[beta], as a reference.
Methods and Results-: Human umbilical vein endothelial cells were stimulated with IL-33 or IL-1[beta], showing highly similar phosphorylation of signaling molecules, induction of adhesion molecules, and transcription profiles. However, intradermally injected IL-33 elicited significantly less proinflammatory endothelial activation when compared with IL-1[beta] and led us to observe that quiescent endothelial cells (ppRblowp27high) were strikingly resistant to IL-33. Accordingly, the IL-33 receptor was preferentially expressed in nonquiescent cells of low-density cultures, corresponding to selective induction of adhesion molecules and chemokines. Multiparameter phosphoflow cytometry confirmed that signaling driven by IL-33 was stronger in nonquiescent cells. Manipulation of nuclear IL-33 expression by siRNA or adenoviral transduction revealed no functional link between nuclear, endogenous IL-33, and exogenous IL-33 responsiveness.
Conclusion-: In contrast to other inflammatory cytokines, IL-33 selectively targets nonquiescent endothelial cells. By this novel concept, quiescent cells may remain nonresponsive to a proinflammatory stimulus that concomitantly triggers a powerful response in cells that have been released from contact inhibition.
(C) 2013 American Heart Association, Inc.