Fibrosarcoma-induced Dysregulation of Interleukin (IL)-1Î² and IL-18 Activities and their Modulation by Paclitaxel
Falwell, Elizabeth Paige
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Cancer remains an elusive killer due, in part, to the suppression of normal immunologic antitumor responses. Normal host (NH) macrophage (MÏ ) populations have tumoricidal effects such as tumor antigen phagocytosis and presentation, and cytokine production. Tumor-infiltrating Mfs may evade these activities by dysregulating production of immunostimulatory cytokines (including Interleukin [IL]-1Î², IL-18, and tumor necrosis factor-Î± [TNF-Î±]), by production of antagonistic factors. The restoration of IL-1Î², IL-18, and TNF-Î± production by MÏ s could re-establish antitumor host immune responses. Previous work in our laboratory suggests that tumor distal (TD) MÏ s produce more IL-1Î² than NH MÏ s when stimulated with IFN-Î³ and lipopolysaccharide (LPS). We hypothesize that the presence of immunomodulatory factors like IL-10 and TGF-Î² dysregulate IL-1Î² production in tumor proximal (TP) MÏ s. Indeed, IL-1Î² production was downregulated among in situ TP MÏ s. We have proposed that IL-18, a structural homologue to IL-1Î² was similarly dysregulated in TD and TP MÏ s. IL-18 was enhanced in both distal and proximal MÏ s. Differences in the functions of these cytokines could account for this dissimilarity. TNF-Î±, another proinflammatory cytokine, followed the dysregulation pattern of IL-1Î² in our tumor-burdened hosts (TBH), likely because of the similar functions of these cytokines. Because it is a potential vehicle for immunotherapeutic treatment, paclitaxelâ s action on the immune response (TAXOLâ ¢) was investigated. Paclitaxel is a potent MÏ activator that upregulates a variety of cytokines in an LPS-like manner. Paclitaxel enhanced TD MÏ production of IL-1Î², IL-18, and TNF-Î± in an LPS-like manner. Production of IL-1Î² and TNF-Î± was reduced in TP MÏ s when treated with paclitaxel; however, IL-18 production was enhanced. This difference could be due to the different functions of IL-1Î² and IL-18. To determine whether production of these cytokines translates into downstream expression of transcription products, IL-12 and nitric oxide (NO) were assayed. NO was enhanced distally, but paclitaxel treatment failed to enhance NO production. When treated with paclitaxel, IL-12 was produced by NH and TD MÏ s. Collectively, these studies suggest that tumor-induced cytokine imbalances compromise antitumor immunity and paclitaxel may reverse this activity.
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