title: IL-32 synergizes with nucleotide oligomerization domain (NOD) 1 and NOD2 ligands for IL-1beta and IL-6 production through a caspase 1-dependent mechanism.
abstract: The activation of innate immunity requires the amplification of signals induced by pattern-recognition receptors for bacterial products. We have investigated the role of the newly described cytokine IL-32 in the amplification of cytokine production induced by the two most clinically relevant families of microbial receptors, the cell-surface Toll-like receptors (TLRs) and the intracellular nuclear oligomerization domain (NOD) receptor family. IL-32 synergized with the NOD1- and NOD2-specific muropeptides of peptidoglycans for the release of IL-1beta and IL-6 (a 3- to 10-fold increase). In contrast, IL-32 did not influence the cytokine production induced via TLRs. The synergistic effect of IL-32 and synthetic muramyl dipeptide (MDP) on cytokine production was absent in the cells of patients with Crohn's disease bearing the NOD2 frameshift mutation 3020insC, demonstrating that the IL-32/MDP synergism depends on NOD2. This in vitro synergism between IL-32 and NOD2 ligands was consistent with a marked constitutive expression of IL-32 in human colon epithelial tissue. In addition, the potentiating effect of IL-32 on the cytokine production induced by the synthetic muropeptide FK-156 was absent in NOD1-deficient macrophages, supporting the interaction between IL-32 and NOD1 pathways. When specific caspase inhibitors were used, the synergism between IL-32 and MDP/NOD2 depended on the activation of caspase 1. Only additive effects of IL-32 and muropeptides were observed for TNF-alpha production. The modulation of intracellular NOD2 pathways by IL-32, but not cell-surface TLRs, and the marked expression of IL-32 in colon mucosa suggest a role of IL-32 in the pathogenesis of Crohn's disease.
authors.affiliation: Divisions of Infectious Diseases and Pulmonary Science and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Tania
authors.initials: T
authors.lastname: Azam
authors.forename: Gerben
authors.initials: G
authors.lastname: Ferwerda
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
authors.forename: Mark
authors.initials: M
authors.lastname: Walsh
authors.forename: Jong-Sung
authors.initials: JS
authors.lastname: Park
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Do-Young
authors.initials: DY
authors.lastname: Yoon
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D020170:Caspase 1 / Q000502:physiology*; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis*; D007378:Interleukins / Q000032:analysis / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008024:Ligands; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C496971:IL32 protein, human; D007375:Interleukin-1; D015850:Interleukin-6; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D051193:Toll-Like Receptors; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D020170:Caspase 1