Journal Article

Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses

Nold-Petry, Claudia A., Hong, Jaewoo, Nold, Marcel F., Bulau, Ana-Maria, Fink, Michaela, Li, Suzhao, Mansell, Ashley, Rubartelli, Anna, Bufler, Philip, Schwerd, Tobias, Dinarello, Charles A.

2014

Overview

IL-37 is a fundamental inhibitor of innate immunity. Human IL-37 has a caspase-1 cleavage site and translocates to the nucleus upon LPS stimulation. Here, we investigated whether caspase-1 processing affects IL-37–mediated suppression of LPS-induced cytokines and the release from cells by analyzing a caspase-1 cleavage site mutant IL-37 (IL-37D20A). Nuclear translocation of IL-37D20A is significantly impaired compared with WT IL-37 in transfected cells. LPS-induced IL-6 was decreased in cells expressing WT IL-37 but not IL-37D20A. The function of IL-37 in transfected bone marrow-derived macrophages is nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-dependent, because IL-37 transfection in apoptosis-associated speck-like protein containing a carboxyl-terminal caspase recruitment domain- and NLRP3-deficient cells does not reduce levels of IL-6 and IL-1β upon LPS stimulation. IL-37–expressing macrophages release both precursor and mature IL-37, but only the externalization of mature IL-37 was dependent on ATP. Precursor and mature IL-37 was also secreted from human dendritic cells and peripheral blood mononuclear cells. To determine whether IL-37 is active in the extracellular compartment, we pretreated IL-37 transgenic mice with IL-37–neutralizing antibodies before LPS challenge. In IL-37–expressing mice, neutralizing IL-37 antibodies reversed the suppression of LPS-induced serum IL-6. In contrast, the addition of neutralizing antibody did not reverse suppression of LPS-induced IL-6 in mouse macrophages transfected with IL-37. Although caspase-1 is required for nuclear translocation of intracellular IL-37 and for secretion of mature IL-37, the release of the IL-37 precursor is independent of caspase-1 activation. IL-37 now emerges as a dual-function cytokine with intra- and extracellular properties for suppressing innate inflammation.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Active Transport, Cell Nucleus - immunology / Adenosine triphosphatase / adenosine triphosphate / Animals / Antibodies, Neutralizing - immunology / Antiinflammatories / Apoptosis / Biological Sciences / blood serum / Blotting, Western / Bone marrow / Caspase 1 - genetics / Caspase 1 - metabolism / caspase-1 / Cell Line / Cell lines / Cell nucleus / Cell Nucleus - metabolism / Cells / Cytokines / dendritic cells / Escherichia coli / Fluorescent Antibody Technique / Humans / Immunity, Innate - immunology / inflammation / innate immunity / Interleukin-1 - metabolism / interleukin-1beta / interleukin-6 / Interleukin-6 - blood / Lipopolysaccharides / Macrophages / Mice / Mice, Transgenic / Microscopy, Confocal / mononuclear leukocytes / Mutagenesis, Site-Directed / mutants / Natural killer cells / neutralization / neutralizing antibodies / oligomerization / Receptors / Rodents / secretion / Stem cells / transfection / transgenic animals / Translocation