Interleukin-32: Frenemy in cancer?

Abstract

Interleukin-32 (IL-32) was originally identified in natural killer (NK) cells activated by IL-2 in 1992. Thus, it was named NK cell transcript 4 (NK4) because of its unknown function at that time. The function of IL-32 has been elucidated over the last decade. IL-32 is primarily considered to be a booster of inflammatory reactions because it is induced by pro-inflammatory cytokines and stimulates the production of those cytokines and vice versa . Therefore, many studies have been devoted to studying the roles of IL-32 in inflammation-associated cancers, including gastric, colon cancer, and hepatocellular carcinoma. At the same time, roles of IL-32 have also been discovered in other cancers. Collectively, IL-32 fosters the tumor progression by nuclear factor-κB (NF-κB)-mediated cytokines and metalloproteinase production, as well as stimulation of differentiation into immunosuppressive cell types in some cancer types. However, it is also able to induce tumor cell apoptosis and enhance NK and cytotoxic T cell sensitivity in other cancer types. In this review, we will address the function of each IL-32 isoform in different cancer types studied to date, and suggest further strategies to comprehensively elucidate the roles of IL-32 in a context-dependent manner.

Local and Systemic Interleukin-32 in Esophageal, Gastric, and Colorectal Cancers: Clinical and Diagnostic Significance

“…IL-32 has been implicated in modulating inflammation, immunity, proliferation, survival, angiogenesis, and epithelial-mesenchymal transition [ 15 ]. Therefore, the pattern of correlation between IL32 expression and a broad spectrum of genes encoding representative proteins implicated in cancer development, namely, IL4 , IL4Ra , IL7 , IL7Ra , IL10 , IL10Ra , IL13 , IL13Ra , ACTA2 , BCL2 , BCLxL , CCL2 , CDKN1A , CLDN2 , SLC2A1 , HIF1A , Ki67 , NOS2 , ODC1 , PTGS2 , TJP1 , and VEGFA , was examined in 45 cancer patients.…”

“…It is expressed in natural killer cells, monocytes, lymphocytes T, peripheral blood mononuclear cells, epithelial and endothelial cells, and fibroblasts in a number of isoforms with varying biological activity. Its expression is triggered by IL-1β, IL-18, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. IL-32 is engaged in setting an inflammatory loop as it in turn induces the synthesis of IL-1β, TNFα, IL-6, IL-8, and macrophage inflammatory protein (MIP)-2 [ 13 , 14 , 15 ]. Consistently, the involvement of IL-32 has been documented in infectious diseases, chronic inflammatory conditions, including gastritis and inflammatory bowel disease, and in cancer [ 13 , 14 , 15 , 16 , 17 , 18 ].…”

“…Amassing evidence indicates that the biological activity of IL-32 is cell type- and context-depended and displays isoform-specific nuances. Consequently, it may either facilitate or hamper cancer development, gaining IL-32 a catching label of “frenemy in cancer” [ 15 ]. Our view on the interleukin shifted from a simple inflammation amplifier to a modulator of inflammatory response and cell fate.…”

“…Our view on the interleukin shifted from a simple inflammation amplifier to a modulator of inflammatory response and cell fate. Importantly, IL-32, as well as mechanisms employed in regulating formation of its endogenous isoforms, is considered a potential target for anti-neoplastic strategy [ 13 , 14 , 15 , 16 ].…”

Bystander CD4+T cells infiltrate human tumors and are phenotypically distinct

“…FOXP3, CTLA4, DUSP4) (33). Interestingly, both Treg and CD39 + CD4 + TILs expressed IL32, a cytokine which enhances NK cell sensitivity and cytotoxicity against tumor cells (34). Furthermore, compared to CD39 + , CD39 -CD4 + TILs expressed more of TNF transcript, suggesting a non-exhausted profile.…”