Interleukin-33, a Novel Member of the IL-1/IL-18 Cytokine Family, in Cardiology and Cardiac Surgery

Abstract

Interleukin-33 is a newly recognized cytokine of the IL-1 family. Unlike its other members IL-1α, IL-1β and IL-18, interleukin-33 induces predominantly Th2-skewed immune responses. In this context, the effects of IL-33 are mostly anti-inflammatory. However, depending on the actual cytokine and cellular milieu, IL-33 can promote both Th1 and Th2 immune reactions. Most importantly for cardiology and cardiac surgery, IL-33 has emerged to represent the as yet unknown ligand of the orphan receptor ST2. Before the advent of IL-33, the ST2 receptor, currently recognized as the soluble one of its two isoforms, was considered to be an unfavorable prognostic marker in myocardial infarction, congestive heart failure and trauma/sepsis shock patients. Now we know that IL-33, when bound to the cellular membrane-anchored ST2L isoform of the receptor, can have certain beneficial effects on the aforementioned conditions. Various forms of IL-33 interaction with the respective isoforms of its cognate receptor are discussed here. The focus is on physiological and prognostic values in cardiac patients.

The IL-33/ST2 Axis Is Associated with Human Visceral Leishmaniasis and Suppresses Th1 Responses in the Livers of BALB/c Mice Infected with Leishmania donovani

“…Interestingly, flow cytometry analysis of the livers of C57BL/6 mice, performed simultaneously, showed lower levels of ST2 MFI (data not shown). Since C57BL/6 mice display a preferential Th1 immune response, whereas BALB/c mice are known to have a Th2-biased genetic background (37), these data are consistent with the widely recognized function of ST2 as a marker associated with Th2 response (38–40). As the balance between Th1 and Th2 responses is critical for VL susceptibility (41–45), we further investigated whether IL-33 could act as a factor of susceptibility associated with Th2 response.…”

Danger Signals Activating the Immune Response after Trauma

“…But unlike IL-1 α and HMGB1, IL-33 exerts repressive transcriptional activity and features some anti-inflammatory properties [82]. IL-33 can activate cells of the innate as well as the adaptive immune system via interaction with membrane ST2, which, in particular, is abundantly expressed on the surface of T helper 2 (Th2) cells and mast cells [83].…”

Soluble ST2 and troponin I combination: Useful biomarker for predicting development of stress cardiomyopathy in patients admitted to the medical intensive care unit

“…sST2 is a member of the Toll-like/interleukin-1 receptor superfamily. 12,13 New insight into sST2 signaling was provided only after the discovery of interleukin-33 (IL-33) as a functional ligand for ST2 in 2005. 14 Both transmembrane and soluble forms of ST2 were upregulated in mechanicallyestimulated cardiac myocytes, with the soluble form displaying more robust expression.…”

“…Stress or strain of cardiac myocytes releases both IL-33 and sST2; elevated IL-33 has cardio-protective effects to reduce fibrosis or hypertrophy, but elevated sST2 blunts that protective effect. 12,13 There have been several studies regarding diagnostic and prognostic values of sST2 in certain cardiac pathologic conditions, such as loss of myocardial tissue (acute myocardial infarction) 15,16 and mechanical overload of the myocardium (heart failure). 17,18 However, none of the previous studies tested sST2 as a cardiac biomarker for SCM, which is also an acute myocardial stress condition.…”