Tristetraprolin (TTP), a mRNA-binding protein, plays a significant role in regulating the expression of adenylate-uridylate-rich elements (AREs) containing messenger RNAs (mRNAs). Mice deficient of TTP (TTP−/−) develop a systemic autoimmune inflammatory syndrome characterized by cachexia, conjunctivitis and dermatitis. Interleukin-12 (IL-12) plays a crucial role in immune defense against infectious and malignant diseases. In the present study, we found increased production of IL-12 during endotoxic shock and enhanced Th1 cells in TTP knockout mice. The levels of IL-12 p70 and p40 protein as well as p40 and p35 mRNA were also increased in activated macrophages deficient of TTP. In line with these findings, overexpression of TTP suppressed IL-12 p35 and p40 expression at the mRNA and promoter level, while surprisingly had little effects on their mRNA stability. Our data showed that the inhibitory effects of TTP on p35 gene transcription were completely rescued by overexpression of NF-κB p65 and c-Rel but not the p50 in activated macrophages. Our data further indicated that TTP acquired its inhibition on IL-12 expression through blocking nuclear translocation of NF-κB p65 and c-Rel while enhancing p50 upon stimulation. In summary, our study reveals a novel pathway through which TTP suppresses IL-12 production in macrophages, resulting in suppression of Th1 cell differentiation. This study may provide us with therapeutic targets for treatment of inflammatory and autoimmune disorders.
PCSK9Is should be strongly considered to improve clinical outcomes in patients at high risk for atherosclerotic CVD.
Introduction: Iodine is an essential micronutrient for thyroid hormone synthesis. Its primary source is fortified foods. Supraphysiologic doses of iodine are often found in iodine supplements that are advertised to support thyroid metabolism and reduce goiter size. Normally, excess iodine temporarily inhibits production of thyroid hormone (Wolff-Chaikoff effect), causing goiter and hypothyroidism. In patients with a pre-existing nodular goiter, the auto-regulation of iodine entry into thyroid cells and thyroid hormone synthesis are ineffective. Exposure to high doses of iodine in such cases can precipitate hyperthyroidism (Jod-Basedow phenomenon). Clinical Case: A 50 year-old lady with morbid obesity, chronic lymphedema, longstanding hypothyroidism, and a large retrosternal goiter presented with severe sepsis from cellulitis and tachycardia-induced cardiomyopathy (ejection fraction 30%) from a new-onset atrial flutter with rapid ventricular rate requiring cardioversion. Free (f)T4 was 4.81 ng/dL (0.93-1.7), fT3 6.0 pg/mL (2.0-4.4) and TSH 0.006 mcu/mL (0.27-4.2). Two years ago, she was seen by endocrinology, at which time TSH was 1.58 mcu/mL on desiccated thyroid 30 mg qd. Due to substernal goiter, surgery was recommended then but declined by the patient. Later, she increased desiccated thyroid to 60mg qd and started OTC iodine supplements at 30,000 mcg qd (20,000% RDA) of her own volition, hoping to decrease the size of the goiter. The patient was subsequently lost to follow-up. On this admission, hospital course was complicated by disseminated intravascular coagulation, acute kidney injury needing renal replacement therapy (RRT), encephalopathy, and mechanical ventilation. CT and US demonstrated stable heterogeneous, multinodular goiter (12.5 x 9.3 cm with mediastinal extension), without prominent vascularity. Treatment with PTU, beta-blockers, hydrocortisone, and cholestyramine was initiated on day 1. Serum iodine was markedly elevated at 2,160 ng/ml (40-92) and improved to 221 ng/ml after six days of RRT. Despite PTU 300mg q6h for > 3 weeks, fT4 remained elevated. Eventually fT3 and fT4 normalized to 2.1pg/mL and 1.30ng/dL, respectively, with continued improvement in iodine level. TSH remained undetectable. Severe medical comorbidities precluded surgical resection of the goiter. Conclusion: Dessicated thyroid hormone, markedly supraphysiologic iodine intake, and thyroid autonomy characteristic of MNG contributed to life-threatening thyrotoxicosis in this patient. Extremely high iodine content in the blood and thyroid undoubtedly impeded therapeutic response to PTU, and RRT helped to lower systemic iodine load. This case demonstrates the importance of careful history taking to identify unusual sources of iodine in patients, and patient education regarding possible dangers associated with unregulated OTC and dietary supplements.
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