Paradoxical effects of constitutive human IL-32γ 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.

Inflammation-dependent secretion and splicing of IL-32γ in rheumatoid arthritis

“…The present study also supports the concept that IL-32 is an example of self-imposed limitation of runaway inflammation by splicing to a less active isoform as well as restricting the product of the IL-32β isoform to an intracellular existence. Transgenic mice expressing human IL-32γ initially exhibit greater inflammation in a model of induced colitis compared with WT but, as the disease progresses, the transgenic mice recover and heal more rapidly than WT (19). It is likely that the splicing event to IL-32β contributes to the clinical improvement.…”

IL-32θ downregulates CCL5 expression through its interaction with PKCδ and STAT3

“…The function of interleukin (IL)-32, formerly named natural killer cell transcript 4 [1], has been previously described in several studies [2][3][4][5][6][7]. The protein sequence of IL-32 is distinct in that it is not homologous with any other cytokines [8].…”

Human IL-32 expression protects mice against a hypervirulent strain of Mycobacterium tuberculosis

“…They reported that IL-32 exacerbated DSS-induced colitis initially but at later time points, there was more rapid healing and less inflammation (20). This spontaneous recovery of IL-32-induced colitis was attributed to secondary induction of IL-10, a cytokine with antiinflammatory effects (20). The authors hypothesized that the increase in IL-10 was due to accumulation of IL-32β, a splice variant of IL-32γ that induces IL-10 (24), an antiinflammatory cytokine also known to predispose mice to MTB (25).…”

“…Choi et al studied dextran sodium sulfate (DSS)-induced colitis using another IL-32γTg strain in which the IL-32γ transgene was under the control of the β-actin promoter and thus expressed ubiquitously (20). They reported that IL-32 exacerbated DSS-induced colitis initially but at later time points, there was more rapid healing and less inflammation (20). This spontaneous recovery of IL-32-induced colitis was attributed to secondary induction of IL-10, a cytokine with antiinflammatory effects (20).…”