title: Paradoxical effects of constitutive human IL-32{gamma} in transgenic mice during experimental colitis.
abstract: Inflammatory cytokines mediate inflammatory bowel diseases (IBDs) and cytokine blocking therapies often ameliorate the disease severity. IL-32 affects inflammation by increasing the production of IL-1, TNFα, and several chemokines. Here, we investigated the role of IL-32 in intestinal inflammation by generating a transgenic (TG) mouse expressing human IL-32γ (IL-32γ TG). Although IL-32γ TG mice are healthy, constitutive serum and colonic tissue levels of TNFα are elevated. Compared with wild-type (WT) mice, IL-32γ TG mice exhibited a modestly exacerbated acute inflammation early following the initiation of dextran sodium sulfate (DSS)-induced colitis. However, after 6 d, there was less colonic inflammation, reduced tissue loss, and improved survival rate compared with WT mice. Associated with attenuated tissue damage, colonic levels of TNFα and IL-6 were significantly reduced in the IL-32γ TG mice whereas IL-10 was elevated. Cultured colon explants from IL-32γ TG mice secreted higher levels of IL-10 compared with WT mice and lower levels of TNFα and IL-6. Constitutive levels of IL-32γ itself in colonic tissues were significantly lower following DSS colitis. Although the highest level of serum IL-32γ occurred on day 3 of colitis, IL-32 was below constitutive levels on day 9. The ability of IL-32γ to increase constitutive IL-10 likely reduces TNFα, IL-6, and IL-32 itself accounting for less inflammation. In humans with ulcerative colitis (UC), serum IL-32 is elevated and colonic biopsies contain IL-32 in inflamed tissues but not in uninvolved tissues. Thus IL-32γ emerges as an example of how innate inflammation worsens as well as protects intestinal integrity.
authors.affiliation: Laboratory of Cytokine Immunology, Medical Immunology Center, Department of Bioscience and Biotechnology, School of Medicine, Konkuk University, Seoul 143-701, Korea.
authors.forename: Jida
authors.initials: J
authors.lastname: Choi
authors.forename: Suyoung
authors.initials: S
authors.lastname: Bae
authors.forename: Jaewoo
authors.initials: J
authors.lastname: Hong
authors.forename: Soyoon
authors.initials: S
authors.lastname: Ryoo
authors.forename: Hyunjhung
authors.initials: H
authors.lastname: Jhun
authors.forename: Kwangwon
authors.initials: K
authors.lastname: Hong
authors.forename: Doyoung
authors.initials: D
authors.lastname: Yoon
authors.forename: Siyoung
authors.initials: S
authors.lastname: Lee
authors.forename: Erk
authors.initials: E
authors.lastname: Her
authors.forename: Wonhyuk
authors.initials: W
authors.lastname: Choi
authors.forename: Jeonghwan
authors.initials: J
authors.lastname: Kim
authors.forename: Tania
authors.initials: T
authors.lastname: Azam
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Soohyun
authors.initials: S
authors.lastname: Kim
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000473:pathology*; D016207:Cytokines / Q000097:blood; D016264:Dextran Sulfate; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D007378:Interleukins / Q000097:blood / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D015996:Survival Rate; D013997:Time Factors
chemical_list: D016207:Cytokines; C496971:IL32 protein, human; D007378:Interleukins; D016264:Dextran Sulfate