Central serotonin (5-HT) is an anorexigenic neurotransmitter in the brain. However, accumulating evidence suggests peripheral 5-HT may affect organismal energy homeostasis. Here we show 5-HT regulates white and brown adipose tissue function. Pharmacological inhibition of 5-HT synthesis leads to inhibition of lipogenesis in epididymal white adipose tissue (WAT), induction of browning in inguinal WAT and activation of adaptive thermogenesis in brown adipose tissue (BAT). Mice with inducible Tph1 KO in adipose tissues exhibit a similar phenotype as mice in which 5-HT synthesis is inhibited pharmacologically, suggesting 5-HT has localized effects on adipose tissues. In addition, Htr3a KO mice exhibit increased energy expenditure and reduced weight gain when fed a high-fat diet. Treatment with an Htr2a antagonist reduces lipid accumulation in 3T3-L1 adipocytes. These data suggest important roles for adipocyte-derived 5-HT in controlling energy homeostasis.

Fas ligand (FasL), perforin, TNF-α, IL-1, and NO have been considered as effector molecule(s) leading to β cell death in autoimmune diabetes. However, the real culprit(s) in β cell destruction have long been elusive, despite intense investigation. We and others have demonstrated that FasL is not a major effector molecule in autoimmune diabetes, and previous inability to transfer diabetes to Fas-deficient nonobese diabetic (NOD)-lpr mice was due to constitutive FasL expression on lymphocytes from these mice. Here, we identified IFN-γ/TNF-α synergism as the final effector molecules in autoimmune diabetes of NOD mice. A combination of IFN-γ and TNF-α, but neither cytokine alone, induced classical caspase-dependent apoptosis in insulinoma and pancreatic islet cells. IFN-γ treatment conferred susceptibility to TNF-α-induced apoptosis on otherwise resistant insulinoma cells by STAT1 activation followed by IFN regulatory factor (IRF)-1 induction. IRF-1 played a central role in IFN-γ/TNF-α-induced cytotoxicity because inhibition of IRF-1 induction by antisense oligonucleotides blocked IFN-γ/TNF-α-induced cytotoxicity, and transfection of IRF-1 rendered insulinoma cells susceptible to TNF-α-induced cytotoxicity. STAT1 and IRF-1 were expressed in pancreatic islets of diabetic NOD mice and colocalized with apoptotic cells. Moreover, anti-TNF-α Ab inhibited the development of diabetes after adoptive transfer. Taken together, our results indicate that IFN-γ/TNF-α synergism is responsible for autoimmune diabetes in vivo as well as β cell apoptosis in vitro and suggest a novel signal transduction in IFN-γ/TNF-α synergism that may have relevance in other autoimmune diseases and synergistic anti-tumor effects of the two cytokines.

Abstract. Primary thyroid lymphoma is a very rare tumor and its prevalence is approximately 0.1% of all thyroid cancers in Korea. Its clinical experience is limited and not familiar to physicians. Therefore, we performed this study to investigate the clinical characteristics of primary thyroid lymphoma in Koreans. We retrospectively analyzed the medical records of the 44 patients with primary thyroid lymphoma from 1991 to 2006 at four major referral hospitals in Korea. Out of 44 patients, eight patients were male and 36 patients were female and their average age was 57 years. Fifty-six percent of patients had underlying Hashimoto's thyroiditis. All but two patients had non-Hodgkin's lymphoma with B cell origin, and eighty percent of patients presented with stage IE or IIE. Twenty-one of 44 patients (48%) had diffuse large B cell lymphoma (DLBCL) and 17 (39%) had MALT lymphoma. Malignancies originating from lymphoid cells were suspected in 10 of eighteen patients with DLBCL (56%) by using fine-needle aspiration cytology (FNAC), and no difference was noted compared with MALT lymphoma (64%). Compared with DLBCL, the patients with MALT lymphoma were more frequently presented with stage I disease (DLBCL vs. MALT lymphoma: 32% vs. 65%, P=0.04). Moreover, in contrast to DLBCL, most of the patients with MALT lymphoma achieved complete response with treatments (DLBCL vs. MALT lymphoma: 53% vs. 94%, P<0.01). Because of the low diagnostic accuracy of FNAC, thyroid biopsy should be considered for the diagnosis of thyroid lymphomas in suspicious cases. The patients with MALT lymphoma were more frequently presented with early stage diseases and this might lead to the favorable outcome to treatments than those with DLBCL.

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