Abstract
PurposeInterleukin 32 (IL-32) is a pro-inflammatory cytokine of which different isoforms have been identified. Recently, IL-32 has been shown to act as a potent inducer of cell migration in several types of cancer. Although previous research showed that IL-32 is expressed in differentiated thyroid cancer (TC) cells, the role of IL-32 in TC cell migration has not been investigated. Furthermore, tumour-associated macrophages (TAMs) may play a facilitating role in cancer cell migration. The aim of this study was to explore whether the interaction between TC cells and TAMs results in increased expression of IL-32 in TC cells and to investigate whether this affects TC cell migration.MethodsTPC-1 cells were co-culture with TC-induced or naive macrophages. Next, transcriptome analysis on TPC-1 cells was performed and supernatants were used for stimulation of TPC-1 cells. IL-32β and IL-32γ were exogenously overexpressed in TPC-1 cells using transient transfection, after which an in vitro gap closure assay was performed to assess cell migration, and the expression of migratory factors was assessed using RT-qPCR.ResultsWe found that TC-induced macrophages induced IL-32 expression in TC cells and that TAM-derived TNFα was the main inducer of IL-32β expression in TC cells. Overexpression of IL-32β and IL-32γ did not affect TC cell migration, but increased cell death. Finally, we found that IL-32β overexpression led to increased mRNA expression of the pro-survival cytokine IL-8, while the expression of other migratory factors was not affected.ConclusionsFrom our data, we conclude that TAM-derived TNFα induces IL-32β in TC cells. Although IL-32β does not affect TC cell migration, alternative splicing of IL-32 towards the IL-32β isoform may be beneficial for TC cell survival through induction of the pro-survival cytokine IL-8.
Highlights
Interleukin 32 (IL-32) is a pro-inflammatory cytokine that has first been described in 2005 [1]
We found that supernatants from TLR-4 stimulated thyroid cancer (TC)-induced macrophages induced significantly higher IL-32α, IL-32β and IL-32γ mRNA expression levels in TPC-1 cells (p = 0.0156) compared to supernatants from RPMI stimulated TC-induced macrophages
Supernatants from TLR-4 stimulated TC-induced macrophages were found to induce in the highest levels of IL-32β, with a fold change of 16.77 ± 6.17 compared to 9.23 ± 5.55 in naive, TLR-4 stimulated monocytes (p = 0.0313)
Summary
Interleukin 32 (IL-32) is a pro-inflammatory cytokine that has first been described in 2005 [1]. IL-32 has been linked to the pathogenesis of several diseases, including inflammatory diseases, cardiovascular diseases and cancer [3,4,5,6,7,8,9]. In the context of cancer, the role of IL-32 seems ambiguous. Other reports indicated that IL-32 may have a more pro-tumorigenic function, especially with respect to mediating invasion and migration in lung, breast and gastric cancers and in osteosarcoma, effects that have not been linked to a specific isoform [13,14,15,16]. IL-32 seems to exert opposite effects in the context of different cell- and cancer types, which depends on which isoform is present [9]
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