A new proinflammatory cytokine interleukin-32 (IL-32) has six isoforms. Although IL-32 can be detected in sera from patients suffering from Crohn's disease and rheumatoid arthritis, it is unclear which isoforms are involved. To this end, we investigated the functions of the most abundant IL-32b by generating K562-IL-32b stable cell lines. This report confirms, using IL-32 small interfering RNA, that IL-32b induces an anti-inflammatory cytokine IL-10 in K562-IL-32b cells and U937 promonocytic cells, which express endogenous IL-32b upon phorbol 12-myristate 13-acetate (PMA) treatment, and monocyte-derived dendritic cells (DC) upon lipopolysaccharide (LPS) treatment. Interleukin-32b was induced in monocyte-derived macrophages by LPS and in monocyte-derived DC by LPS, poly(I:C), or anti-CD40 antibody, but was not induced by PMA. We showed that IL-32b expression was increased in a time-dependent manner in monocyte-derived DC upon LPS treatment and peaked at 24 hr. Production of IL-10 was exactly coincident with IL-32b expression, but IL-1b and tumour necrosis factor-a production peaked at 6 hr after LPS treatment, then steeply declined. Interleukin-12 p40 was induced at 9 hr and gradually increased until 48 hr, at which time IL-32b and IL-10 were no longer increased. Knock-down of IL-32b by IL-32 small interfering RNA led to the decrease of IL-10, but the increase of IL-12 in monocytederived DC, which means that IL-32b promotes IL-10 production, but limits IL-12 production. We also showed that IL-10 neutralization increases IL-12, IL-1b and tumour necrosis factor-a production, which implies that IL-10 suppresses such proinflammatory cytokines. Taken together, our results suggest that IL-32b upregulates the production of an anti-inflammatory cytokine IL-10, and then IL-10 suppresses proinflammatory cytokines.Keywords: cytokine; dendritic cell; inflammation; interleukin-10; interleukin-32Please cite this article in press as: Kang J.-W. et al. A proinflammatory cytokine interleukin-32b promotes the production of an anti-inflammatory cytokine interleukin-10, Immunology (2009)

Overweight and obesity lead to an increased risk for metabolic disorders such as impaired glucose regulation/insulin resistance, dyslipidemia, and hypertension. Several molecular drug targets with potential to prevent or treat metabolic disorders have been revealed. Interestingly, the activation of peroxisome proliferator-activated receptor (PPAR), which belongs to the nuclear receptor superfamily, has many beneficial clinical effects. PPAR directly modulates gene expression by binding to a specific ligand. All PPAR subtypes (α, γ, and σ) are involved in glucose metabolism, lipid metabolism, and energy balance. PPAR agonists play an important role in therapeutic aspects of metabolic disorders. However, undesired effects of the existing PPAR agonists have been reported. A great deal of recent research has focused on the discovery of new PPAR modulators with more beneficial effects and more safety without producing undesired side effects. Herein, we briefly review the roles of PPAR in metabolic disorders, the effects of PPAR modulators in metabolic disorders, and the technologies with which to discover new PPAR modulators.

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Summary Studies have demonstrated that the anti‐tumour effect of natural killer (NK) cells is successful for patients with several cancers. Although interleukin‐32 (IL‐32) is endogenously expressed in NK cells, cytolytic function of NK cells against cancer cells has not been fully demonstrated. In the present study, we found that the growth of cancer cells was suppressed when colon cancer cells or prostate cancer cells were co‐cultured with NK‐92 cells, an NK cell line. We also found that the expression of tumour necrosis factor receptor 2 and death receptor 3 (DR3) was increased in PC3 cells, and the expression of FAS and DR3 was increased in SW620 cells by co‐culture with NK‐92 cells. However, cancer cell growth inhibition and IL‐32 expression were abolished when cancer cells were co‐cultured with NK cells transfected with small interfering (si) RNA of IL‐32. DR3 expression was also diminished by co‐culture with IL‐32‐specific siRNA‐transfected NK‐92 cells. Expression of APO3L, a ligand of DR3, was elevated in NK cells that were co‐cultured with cancer cells. It was also found that expression of apoptosis‐related proteins such as cleaved caspase‐3 and bax was increased in cancer cells co‐cultured with NK‐92 cells, but their expression was abolished by co‐culture with IL‐32 siRNA‐transfected NK‐92 cells. Moreover, knockdown of DR3 in co‐culture of NK‐92 cells with cancer cells by siRNA or antibodies of DR3 and APO3L reversed the growth inhibitory effect of NK‐92 cells. In conclusion, our study showed that IL‐32 enhanced the cytotoxic effect of NK‐92 cells on the cancer cells through activation of DR3 and caspase‐3.