Altered serum levels of IL-33 in patients with advanced systolic chronic heart failure: correlation with oxidative stress

Abstract

BackgroundInterleukin-33 (IL-33) has been linked to chronic heart failure (CHF) in animal studies, but data on serum IL-33 levels in human CHF are not available. We analyzed levels of IL-33 in serum, and investigated the possible role of IL-33 in oxidative stress.MethodsA total of 191 subjects with advanced systolic CHF (CHF group), 175 patients with pre-existing cardiac diseases but no CHF (non-CHF group), and 177 healthy controls (HC group) were enrolled. Serum levels of IL-33, soluble ST2 (sST2) and N-terminal-pro-brain natriuretic peptide (NT-proBNP), malondialdehyde (MDA) content, erythrocyte superoxide dismutase (eSOD) activity, as well as left ventricular ejection fraction (LVEF), were determined. The exact form of IL-33 in serum was identified. Effects of IL-33 and sST2 on MDA content and SOD activity in angiotensin (Ang II)-stimulated AC16 cells were assessed.ResultsSerum levels of IL-33 and sST2 were elevated in CHF patients, whereas IL-33/sST2 ratios were decreased. In CHF patients, pre-existing cardiac diseases and medications used upon hospital admission did not affect IL-33 concentrations or the IL-33/sST2 ratio. Full-length IL-33, which could not be detected in serum from HC and barely detected in non-CHF patients, was significantly up-regulated in CHF patients. IL-33 levels were positively correlated with markers of CHF severity. IL-33/sST2 ratios were slightly and negatively related to MDA concentrations. IL-33 directly reduced MDA and enhanced SOD activity in Ang II-stimulated AC16 cells, which were greatly attenuated by sST2.ConclusionsSerum levels of IL-33, especially the full-length form, were elevated in CHF patients whereas IL-33 bioactivity was reduced. In advanced CHF, IL-33 may exert anti-oxidation effects, which may be overwhelmed by concurrently elevated levels of sST2.

Protection against oxidative stress by vitamin D in cone cells

“…The suppression of IL‐18 gene expression is believed to be mediated by the downregulation of the transcription factor NF‐KB activation as a direct interaction with IκB kinase α and β (IkKα/β) which in turn raises the level of cytoplasmic NFkB‐p65/p50 leading to gene transactivation . IL‐33 is classified as an IL‐1 cytokine family with anti‐inflammatory and anti‐oxidative stress properties . Our current finding has demonstrated that the expression of IL‐33 gene (Figure F) in 661W cells exposed to strong oxidative stimuli like H 2 O 2 was markedly inhibited compared to that of untreated cells.…”

“…As demonstrated in Figure the expression levels of TNF‐α, IL‐1β and IL‐18 were considerably increased in cells treated with H 2 O 2 compared to that of control cells at 6 and 24 h. However, the expression of these genes was significantly repressed after 1,α, 25‐dihydroxyvitamin D 3 treatment. Accumulated data have concluded that the 1,α, 25‐dihydroxyvitamin D 3 and its VDR exert an anti‐inflammatory effect on the expression of such gene in vivo and in vitro via gene regulation of some key pathways such as nuclear factor kappa B (NF‐KB), extracellular signal‐regulated kinases (ERK1/2), c‐jun N‐terminal protein kinases (c‐JNK) and the p38 protein kinases (P38) of the MAPK pathway which broadly controls inflammatory signalling during inflammatory response . The TNF‐α is a pleiotropic pro‐inflammatory cytokine that implicates in many immune responses in activated cells.…”

“…In a recent study, Zhang et al . have investigated the inhibitory effect of 1,α, 25‐dihydroxyvitamin D 3 on TNF‐α gene expression in human monocyte cell line and C57BL/6 mice which concluded that the 1,α, 25‐dihydroxyvitamin D 3 can upregulate MAPK phosphatase‐1 (MKP1), a key regulatory enzyme that dephosphorylates p38 MAPK resulting downexpression of TNF‐α gene . Similarly, the expression of IL‐1β gene in human HCT116 and Hke‐3 colorectal carcinoma and THP1 monocyte cell lines has been reported to be suppressed by 1,α, 25‐dihydroxyvitamin D 3 treatment .…”

“…Accumulated data have concluded that the 1,α, 25-dihydroxyvitamin D 3 and its VDR exert an anti-inflammatory effect on the expression of such gene in vivo and in vitro via gene regulation of some key pathways such as nuclear factor kappa B (NF-KB), extracellular signal-regulated kinases (ERK1/2), c-jun N-terminal protein kinases (c-JNK) and the p38 protein kinases (P38) of the MAPK pathway which broadly controls inflammatory signalling during inflammatory response. 19,[42][43][44][45] The TNF-α is a pleiotropic pro-inflammatory cytokine that implicates in many immune responses in activated cells. In a recent study, Zhang et al have investigated the inhibitory effect of 1,α, 25-dihydroxyvitamin D 3 on TNF-α gene expression in human monocyte cell line and C57BL/6 mice which concluded that the 1,α, 25-dihydroxyvitamin D 3 can upregulate MAPK phosphatase-1 (MKP1), a key regulatory enzyme that dephosphorylates p38 MAPK resulting downexpression of TNF-α gene.…”

The IL-33/ST2 axis: Role in health and disease

“…Indeed, in a murine model of allergic inflammation, allergen exposure induced inflammation and high sST2 levels in serum, whereas sST2-pretreated mice showed reduced lung inflammation [45]. Increased sST2 serum levels have been described in several chronic diseases, such as inflammatory bowel diseases, asthma, and chronic heart failure [8,46,47].…”