Several studies have shown physiological functions of interleukin (IL)-32, a novel cytokine. However, the role of IL-32 in cancer development has not been reported. In this study, we showed that IL-32γ inhibited tumor growth in IL-32γ-overexpressing transgenic mice inoculated with melanoma as well as colon tumor growth in xenograft nude mice inoculated with IL-32γ-transfected colon cancer cells (SW620). The inhibitory effect of IL-32γ on tumor growth was associated with the inhibition of constitutive activated nuclear transcription factor-κB (NF-κB) and of signal transducer and activator of transcription 3 (STAT3). The expression of antiapoptotic, cell proliferation and tumor-promoting genes (bcl-2, X-chromosome inhibitor of apoptosis protein (IAP), cellular IAP and cellular FADD-like IL-1β-converting enzyme-inhibitory protein, cyclin D), cyclin-dependent kinase 4, cycolooxygenase-2 and inducible nitric oxide synthase was decreased, whereas the expression of apoptotic target genes (caspase-3 and -9, bax) increased. In tumor, spleen and blood, the number of cytotoxic CD8+ T cells and CD57+ natural killer cells and the levels of IL-10 increased, but that of tumor necrosis factor-α (TNF-α), IL-1β and IL-6 decreased. We also found that forced overexpression of IL-32γ inhibited colon cancer cell (SW620 and HCT116) growth accompanied with the inhibition of activated NF-κB and STAT3 in vitro. In addition, when IL-32γ was knocked down by small interfering RNA (siRNA) or neutralized with an anti-IL-32γ antibody, IL-32γ-induced colon cancer cell growth inhibition, the IL-32γ-induced decrease of TNF-α, IL-1 and IL-6 production, and the increase of IL-10 production were abolished. However, siRNA of NF-κB and STAT3 augmented IL-32γ-induced colon cancer cell growth inhibition. These findings indicate significant pathophysiological roles of IL-32γ in cancer development.
IntroductionSulfur compounds isolated from garlic exert anti-inflammatory properties. We recently isolated thiacremonone, a novel sulfur compound from garlic. Here, we investigated the anti-inflammatory and arthritis properties of thiacremonone through inhibition of NF-κB since NF-κB is known to be a target molecule of sulfur compounds and an implicated transcription factor regulating inflammatory response genes.MethodsThe anti-inflammatory and arthritis effects of thiacremone in in vivo were investigated in 12-O-tetradecanoylphorbol-13-acetate-induced ear edema, carrageenan and mycobacterium butyricum-induced inflammatory and arthritis models. Lipopolysaccharide-induced nitric oxide (NO) production was determined by Griess method. The DNA binding activity of NF-κB was investigated by electrophoretic mobility shift assay. NF-κB and inducible nitric oxide synthetase (iNOS) transcriptional activity was determined by luciferase assay. Expression of iNOS and cyclooxygenase-2 (COX-2) was determined by western blot.ResultsThe results showed that topical application of thiacremonone (1 or 2 μg/ear) suppressed the 12-O-tetradecanoylphorbol-13-acetate-induced (1 μg/ear) ear edema. Thiacremonone (1-10 mg/kg) administered directly into the plantar surface of hind paw also suppressed the carrageenan (1.5 mg/paw) and mycobacterium butyricum (2 mg/paw)-induced inflammatory and arthritic responses as well as expression of iNOS and COX-2, in addition to NF-κB DNA-binding activity. In further in vitro study, thiacremonone (2.5-10 μg/ml) inhibited lipopolysaccharide (LPS, 1 μg/ml)-induced nitric oxide (NO) production, and NF-κB transcriptional and DNA binding activity in a dose dependent manner. The inhibition of NO by thiacremonone was consistent with the inhibitory effect on LPS-induced inducible nitric oxide synthase (iNOS) and COX-2 expression, as well as iNOS transcriptional activity. Moreover, thiacremonone inhibited LPS-induced p50 and p65 nuclear translocation, resulting in an inhibition of the DNA binding activity of the NF-κB. These inhibitory effects on NF-κB activity and NO generation were suppressed by reducing agents dithiothreitol (DTT) and glutathione, and were abrogated in p50 (C62S)-mutant cells, suggesting that the sulfhydryl group of NF-κB molecules may be a target of thiacremonone.ConclusionsThe present results suggested that thiacremonone exerted its anti-inflammatory and anti-arthritic properties through the inhibition of NF-κB activation via interaction with the sulfhydryl group of NF-κB molecules, and thus could be a useful agent for the treatment of inflammatory and arthritic diseases.
Cytokine and activation of lymphocytes are critical for tumor growth. We investigated whether interleukin (IL)-32β overexpression changes other cytokine levels and activates cytotoxic lymphocyte, and thus modify tumor growth. Herein, IL-32β inhibited B16 melanoma growth in IL-32β-overexpressing transgenic mice (IL-32β mice), and downregulated the expressions of anti-apoptotic proteins (bcl-2, IAP, and XIAP) and cell growth regulatory proteins (Ki-67 antigen (Ki-67) and proliferating cell nuclear antigen (PCNA)), but upregulated the expressions of pro-apoptotic proteins (bax, cleaved caspase-3, and cleaved caspase-9). IL-32β also inhibited colon and prostate tumor growth in athymic nude mice inoculated with IL-32β-transfected SW620 colon or PC3 prostate cancer cells. The forced expression of IL-32β also inhibited cell growth in cultured colon and prostate cancer cells, and these inhibitory effects were abolished by IL-32 small interfering RNA (siRNA). IL-10 levels were elevated, but IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) levels were reduced in the tumor tissues and spleens of IL-32β mice, and athymic nude mice. The number of cytotoxic T (CD8+) and natural killer (NK) cells in tumor tissues, spleen, and blood was significantly elevated in IL-32β mice and athymic nude mice inoculated with IL-32β-transfected cancer cells. Constituted activated NF-κB and STAT3 levels were reduced in the tumor tissues of IL-32β mice and athymic nude mice, as well as in IL-32β-transfected cultured cancer cells. These findings suggest that IL-32β inhibits tumor growth by increasing cytotoxic lymphocyte numbers, and by inactivating the NF-κB and STAT3 pathways through changing of cytokine levels in tumor tissues.
Hyponatremia (sodium levels of <135 mEq/L) is one of the most common electrolyte imbalances in clinical practice, especially in patients with neurologic diseases. Hyponatremia can cause cerebral edema and brain herniation; therefore, prompt diagnosis and proper treatment is important in preventing morbidity and mortality. Among various causes of hyponatremia, diagnosing syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral/renal salt wasting syndrome (C/RSW) is difficult due to many similarities. SIADH is caused by excess of renal water reabsorption through inappropriate antidiuretic hormone secretion, and fluid restriction is the treatment of choice. On the other hand, C/RSW is caused by natriuresis, which is followed by volume depletion and negative sodium balance and replacement of water and sodium is the mainstay of treatment. Determinating volume status in hyponatremic patients is the key point in differential between SIADH and C/RSW. However, in most situations, differential diagnosis of these two diseases is difficult because they overlap in many clinical and laboratory aspects, especially to assess differences in volume status of these patients. Although distinction between the SIADH and C/RSW is difficult, improvement of hypouricemia and an increased fractional excretion of uric acid after the correction of hyponatremia in SIADH, not in C/RSW, may be one of the helpful points in discriminating the two diseases. In this review, we compare these two diseases regarding the pathophysiologic mechanisms, diagnosis, and therapeutic point of view.
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