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Abstract
BackgroundRenal cell carcinoma (RCC) is one of the most common kidney cancers and is highly resistant to chemotherapy. Accumulating evidence suggests that interleukin-22 (IL-22) may mediate host defense against varietal pathogens as a proinflammatory and anti-inflammatory cytokine. The purpose of this study is to assess the inhibitory effects of IL-22 on human RCC cell line A498 and to investigate the possible mechanisms underlying the anti-tumor effects of this cytokine.MethodologyA498 cells, a RCC cell line, were used to assess the inhibitory growth effects of IL-22 using the MTT assay and flow cytometric analysis in vitro. BALB/C nude mice bearing A498 cell xenografts were used to examine the antitumor efficacy of IL-22 in vivo. Western blotting assay was performed to detect the regulation of the intracellular signaling pathway of IL-22.Principal FindingsWe found that IL-22 suppressed the growth of A498 cells in a dose-dependent manner and inhibited the growth of A498 xenografts. We also observed that IL-22 produced a dose-dependent inhibitory effect on A498 cells that involved the induction of G2/M cell cycle arrest without cell apoptosis. Moreover, we showed that the phosphorylation of STAT1 was increased and the phosphorylation of ERK1/2 was attenuated in A498 cells exposed to IL-22. The growth inhibition of A498 cells was partially revised after IL-22 treatment as the expression of STAT1 was knocked down. And inflammatory cytokines, interferon-α and tumor necrosis factor-α (TNF-α) were barely involved in the suppression of A498 cell xenografts treated with IL-22.ConclusionsIL-22 dose-dependently suppresses RCC cell line A498 cells in vitro and induces growth inhibition of A498 cell-bearing mouse xenografts. These results suggest that the anti-RCC effects of IL-22 are at least partially mediated through regulation of STAT1 signaling pathways and G2/M cell cycle arrest, rather than by inducing apoptosis and inflammatory cytokines.
Highlights
Renal cell carcinoma (RCC) is one of the most common malignant tumors arising in the kidney [1,2]; chemotherapeutic agents typically have little or no impact on this type of tumor [3,4,5]
IL-22 dose-dependently suppresses RCC cell line A498 cells in vitro and induces growth inhibition of A498 cellbearing mouse xenografts. These results suggest that the anti-RCC effects of IL-22 are at least partially mediated through regulation of signal transducer and activator of transcription 1 (STAT1) signaling pathways and G2/M cell cycle arrest, rather than by inducing apoptosis and inflammatory cytokines
We investigated the effects of IL-22 on human RCC cell line A498 cells in vitro and in vivo and studied the possible mechanisms underlying the anti-tumor effects of this cytokine
Summary
RCC is one of the most common malignant tumors arising in the kidney [1,2]; chemotherapeutic agents typically have little or no impact on this type of tumor [3,4,5]. Immunotherapy with interleukin 2 (IL-2) and interferona (IFN-a) has been the standard treatment in patients with metastatic RCC, the response rate of patients with the disease to such treatment is only 10,20%, and the addition of the chemotherapeutic agent 5-FU does not notably increase the survival rate [8,9,10]. IL-22 mediates its effects via a heterodimeric transmembrane receptor complex consisting of IL-22R and IL-10R2. It sequentially regulates several intracellular signal pathways including Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathways including STAT3, Jak and Tyk2 [22,23,24,25]. The purpose of this study is to assess the inhibitory effects of IL-22 on human RCC cell line A498 and to investigate the possible mechanisms underlying the anti-tumor effects of this cytokine
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