Abstract
Interleukin (IL)-33 is an interleukin-1 like cytokine that enhances Th2 responses and mediates mucosal immunity and allergic inflammation but the mechanism regulating endogenous IL-33 production are still under investigation. In macrophages, lipopolysaccharide (LPS) administration resulted in marked induction of IL-33 mRNA that was blunted in macrophages from glutaredoxin-1 (Glrx) knockout mice and in RAW264.7 macrophages with Glrx knockdown by siRNA. Glutaredoxin-1 is a small cytosolic thioltransferase that controls a reversible protein thiol modification, S-glutationylation (protein-GSH adducts), thereby regulating redox signaling. In this study, we examined the mechanism of Glrx regulation of endogenous IL-33 induction in macrophages. Glrx knockdown resulted in impaired de-glutathionylation of TRAF6, which is required for TRAF6 activation, and inhibited downstream IKKβ and NF-κB activation. Inhibitors of NF-κB suppressed IL-33 induction and chromatin IP sequencing data analysis confirmed that IL-33 is an NF-κB-responsive gene. Since TRAF6-NF-κB activation is also essential for IL-33 signaling through its receptor, ST2L, we next tested the involvement of Glrx in exogenous IL-33 responses in RAW264.7 cells. Recombinant IL-33 (rIL-33) administration induced IL-33 mRNA expression in RAW264.7 macrophages, and this was inhibited by Glrx knockdown. Interestingly, rIL-33-induced IL-33 protein was identified as the 20 kDa cleaved form whereas LPS-induced IL-33 protein was identified as full-length IL-33, which may be less active than the cleaved form. In a clinically-relevant mouse model of asthma, intra-tracheal cockroach antigen treatment induced Glrx protein in wild type mouse lungs but Glrx induction was attenuated in IL-33 knockout mouse lungs, suggesting that IL-33 may regulate Glrx induction in vivo in response to allergen challenge. In summary, our data reveal a novel mechanism by which Glrx controls both LPS- and IL-33-mediated NF-κB activation leading to IL-33 production, and paracrine IL-33 can induce Glrx to further regulate inflammatory reactions.
Highlights
IntroductionIL-33 is a member of the IL-1 family that was identified as the ligand of the orphan receptor, ST2L (formal name, IL-1 receptor-like 1, IL1RL1), and transduces signals through transmembrane ST2L receptor via TNF receptor-associated factor 6 (TRAF6) [1]
IL-33 is a member of the IL-1 family that was identified as the ligand of the orphan receptor, ST2L, and transduces signals through transmembrane ST2L receptor via TNF receptor-associated factor 6 (TRAF6) [1]
After exposure to LPS (100 ng/ml) for 6 hours, IL-33 was highly induced by LPS in wild type (WT) cells and this induction was strikingly inhibited in Glrx KO cells. (Fig 1A) WT basal expression equal to 1; WT + LPS was 2454 ± 168 and KO + LPS was 171 ± 26, n = 3, p
Summary
IL-33 is a member of the IL-1 family that was identified as the ligand of the orphan receptor, ST2L (formal name, IL-1 receptor-like 1, IL1RL1), and transduces signals through transmembrane ST2L receptor via TNF receptor-associated factor 6 (TRAF6) [1]. IL-33 is known to enhance Th2 responses and mediate allergic reactions [1,2]. Endogenous IL-33 contributes to innate-type mucosal immunity and allergic airway inflammation [3,4,5]. Alternaria alternata exposure in the airways of mice and in vitro induces rapid release of IL-33 by epithelial cells into the extracellular milieu. In this setting, ATP mediated activation of purinergic receptors and sustained increases in calcium are responsible for IL-33 release both in vitro and in vivo [11]
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