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: Jida Choi, Suyoung Bae, Jaewoo Hong, Soyoon Ryoo, Hyunjhung Jhun, Kwangwon Hong, Doyoung Yoon, Siyoung Lee, Erk Her, Wonhyuk Choi, Jeonghwan Kim, Tania Azam, Charles A Dinarello, Soohyun Kim
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 49 Pg. 21082-6 (Dec 07 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 21078994 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• IL32 protein, human
• Interleukins
• Dextran Sulfate

Topics

• Animals
• Colitis (chemically induced, pathology)
• Cytokines (blood)
• Dextran Sulfate
• Humans
• Inflammation (etiology)
• Interleukins (blood, physiology)
• Mice
• Mice, Transgenic
• Survival Rate
• Time Factors