Identification of the most active interleukin‐32 isoform

Choi, Jida; Bae, Sang Rak; Hong, Jaewoo; Azam, Tania; Dinarello, Charles A.; Her, Erk; Choi, Whan-Soo; Kim, Bokyung; Lee, Chang-Kwon; Yoon, Do‐Young; Kim, Sun‐Jong; Kim, Soohyun

doi:10.1111/j.1365-2567.2008.02917.x

Cited by 157 publications

(165 citation statements)

References 29 publications

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“…Among the isoforms tested (a, b, and g), IL-32g, the longest isoform, was the most potent inducer of IKKa/b phosphorylation, IkB degradation, and p38 activation (Fig. 1A), as has been observed in other cell culture systems (32). Thus, we selected IL-32g for the subsequent experiments.…”

Section: Resultsmentioning

confidence: 69%

M-CSF Inhibits Anti–HIV-1 Activity of IL-32, but They Enhance M2-like Phenotypes of Macrophages

Osman

Bhuyan

Hashimoto

et al. 2014

The Journal of Immunology

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M-CSF promotes the differentiation and survival of macrophages, and preferentially induces anti-inflammatory M2, rather than proinflammatory M1 macrophages. Recently, another cytokine, IL-32, was also shown to promote macrophage differentiation. In this article, we provide the first evidence, to our knowledge, that M-CSF has both additive and inhibitory effects on the macrophage-related activities of IL-32. When added to M-CSF–derived macrophages, M-CSF and IL-32 promoted macrophage survival, which was further enhanced by their combination. However, they had different effects on HIV-1 replication; that is, it was stimulated by M-CSF and inhibited by IL-32. Interestingly, the anti–HIV-1 activity of IL-32 was counteracted by M-CSF. Such inhibitory effect of M-CSF was not observed with IL-32–induced M1-like features including high cytokine/chemokine production and strong expression of the costimulatory molecule CD80. However, IL-32–treated macrophages unexpectedly showed also M2-like features including increased phagocytic activity, and high expression of CD14 and the scavenger receptor CD163, and the expression of CD14 and CD163 was further upregulated by cotreatment with M-CSF. The findings of this study regarding the unique functional interplay between M-CSF and IL-32 increase our understanding of the mechanisms that regulate the survival and M1/M2 ratio of macrophages, as well as HIV-1 replication in macrophages.

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Section: Resultsmentioning

confidence: 69%

M-CSF Inhibits Anti–HIV-1 Activity of IL-32, but They Enhance M2-like Phenotypes of Macrophages

Osman

Bhuyan

Hashimoto

et al. 2014

The Journal of Immunology

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“…Samples were immunoblotted with affinity-purified goat anti-human IL-32γ antibody and a rabbit antibody against β-actin (Santa Cruz Biotechnology) as described (7).…”

Section: Methodsmentioning

confidence: 99%

“…IL-32 was first reported as an inducer of TNFα (6), particularly the IL-32γ isoform (7). IL-32 also induces IL-1β, IL-6, and MIP-2 in cell lines and primary cells (6,(8)(9)(10)(11)(12).…”

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confidence: 99%

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Paradoxical effects of constitutive human IL-32γ in transgenic mice during experimental colitis

Choi

Bae

Hong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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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.

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“…There are six splice variants (IL-32a, IL-32b, IL-32g, IL-32d, IL-32ε, and IL-32j), among which the g isoform of IL-32 is the longest one with the most prominent biological activity (25). IL-32 plays an important role in innate and adaptive immune responses.…”

mentioning

confidence: 99%

IL-32γ Induces the Maturation of Dendritic Cells with Th1- and Th17-Polarizing Ability through Enhanced IL-12 and IL-6 Production

Jung

Son

Kim

et al. 2011

The Journal of Immunology

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IL-32, a newly described multifunctional cytokine, has been associated with a variety of inflammatory diseases, including rheumatoid arthritis, vasculitis, and Crohn’s disease. In this study, we investigated the immunomodulatory effects of IL-32γ on bone marrow-derived dendritic cell (DC)-driven Th responses and analyzed the underlying signaling events. IL-32γ–treated DCs exhibited upregulated expression of cell-surface molecules and proinflammatory cytokines associated with DC maturation and activation. In particular, IL-32γ treatment significantly increased production of IL-12 and IL-6 in DCs, which are known as Th1- and Th17-polarizing cytokines, respectively. This increased production was inhibited by the addition of specific inhibitors of the activities of phospholipase C (PLC), JNK, and NF-κB. IL-32γ treatment increased the phosphorylation of JNK and the degradation of both IκBα and IκBβ in DCs, as well as NF-κB binding activity to the κB site. The PLC inhibitor suppressed NF-κB DNA binding activity and JNK phosphorylation increased by IL-32γ treatment, thereby indicating that IL-32γ induced IL-12 and IL-6 production in DCs via a PLC/JNK/NF-κB signaling pathway. Importantly, IL-32γ–stimulated DCs significantly induced both Th1 and Th17 responses when cocultured with CD4+ T cells. The addition of a neutralizing anti–IL-12 mAb abolished the secretion of IFN-γ in a dose-dependent manner; additionally, the blockage of IL-1β and IL-6, but not of IL-21 or IL-23p19, profoundly inhibited IL-32γ–induced IL-17 production. These results demonstrated that IL-32γ could effectively induce the maturation and activation of immature DCs, leading to enhanced Th1 and Th17 responses as the result of increased IL-12 and IL-6 production in DCs.

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Identification of the most active interleukin‐32 isoform

Cited by 157 publications

References 29 publications

M-CSF Inhibits Anti–HIV-1 Activity of IL-32, but They Enhance M2-like Phenotypes of Macrophages

M-CSF Inhibits Anti–HIV-1 Activity of IL-32, but They Enhance M2-like Phenotypes of Macrophages

Paradoxical effects of constitutive human IL-32γ in transgenic mice during experimental colitis

IL-32γ Induces the Maturation of Dendritic Cells with Th1- and Th17-Polarizing Ability through Enhanced IL-12 and IL-6 Production

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