IL-37 is a fundamental inhibitor of innate immunity. Human IL-37 has a caspase-1 cleavage site and translocates to the nucleus upon LPS stimulation. Here, we investigated whether caspase-1 processing affects IL-37-mediated suppression of LPS-induced cytokines and the release from cells by analyzing a caspase-1 cleavage site mutant IL-37 (IL-37D20A). Nuclear translocation of IL-37D20A is significantly impaired compared with WT IL-37 in transfected cells. LPS-induced IL-6 was decreased in cells expressing WT IL-37 but not IL-37D20A. The function of IL-37 in transfected bone marrowderived macrophages is nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-dependent, because IL-37 transfection in apoptosis-associated speck-like protein containing a carboxyl-terminal caspase recruitment domain-and NLRP3-deficient cells does not reduce levels of IL-6 and IL-1β upon LPS stimulation. IL-37-expressing macrophages release both precursor and mature IL-37, but only the externalization of mature IL-37 was dependent on ATP. Precursor and mature IL-37 was also secreted from human dendritic cells and peripheral blood mononuclear cells. To determine whether IL-37 is active in the extracellular compartment, we pretreated IL-37 transgenic mice with IL-37-neutralizing antibodies before LPS challenge. In IL-37-expressing mice, neutralizing IL-37 antibodies reversed the suppression of LPS-induced serum IL-6. In contrast, the addition of neutralizing antibody did not reverse suppression of LPS-induced IL-6 in mouse macrophages transfected with IL-37. Although caspase-1 is required for nuclear translocation of intracellular IL-37 and for secretion of mature IL-37, the release of the IL-37 precursor is independent of caspase-1 activation. IL-37 now emerges as a dual-function cytokine with intra-and extracellular properties for suppressing innate inflammation. W ith the exception of the IL-1 receptor antagonist, members of the IL-1 family are first synthesized as precursor molecules containing a propeptide domain lacking a classical signal sequence (1). Caspase-1 has emerged as the main intracellular processing enzyme responsible for maturation of active IL-1β and IL-18, which are then released into the extracellular space, as shown for IL-1β and IL-18 (2, 3). The IL-1 family member IL-37 is also synthesized as a precursor and is processed to its mature form upon LPS treatment (4, 5). Caspase-1 seems to be the main enzyme responsible for the in vitro maturation of IL-37 in comparison to caspase-4 and granzyme B (4). A putative cleavage site for caspase-1 is located in exon 1 between residues D20 and E21 of IL-37 (4). HEK 293 or CHO cells transfected with the IL-37 precursor release IL-37 starting at amino acid V46, suggesting a second cleavage site in the sequence encoded by exon 2 (6). We previously demonstrated that processing of IL-37 is only partially inhibited by caspase-1 inhibitors, indicating that caspase-1 is not the only enzyme responsible for the processing of IL-37 (5)...

We recently reported that after LPS stimulation, IL-37 translocates to the nucleus and reduces the expression of proinflammatory cytokines. The aim of this study was to investigate whether transiently expressed IL-37 in mice reduces inflammation in concanavalin A (ConA)-induced hepatitis and LPS-induced sepsis. Transgene IL-37 expression was detected in the liver lysate of mice injected with IL-37 plasmid-DNA after hydrodynamic tail vein injection. All mice developed severe acute hepatitis after ConA injection. No difference in the histological score and serum ALT was observed between the two groups that might be explained by patchy expression of IL-37 protein in the liver. However, 2 hrs after ConA injection, serum levels for IL-1α, IL-6, IL-5, and IL-9 were significantly reduced in IL-37-expressing mice as seen for the LPS model. In conclusion, in vivo expression of human IL-37 in mice reduces local and systemic inflammation in ConA-induced hepatitis and LPS challenge.

Most preterm infant formulas contain mediumchain triacylglycerols (MCT), but the effects of MCT on polyunsaturated fatty acid status and metabolism are controversial. Thus, we studied the effects of MCT on linoleic acid metabolism using stable isotopes. Enterally fed preterm infants were randomized to receive for 7 days 40% of fat as MCT (n ‫؍‬ 10) or a formula without MCT (n ‫؍‬ 9). At study day 5, infants received orally 2 mg/kg body weight of 13 C-labeled linoleic acid. Fatty acids in plasma lipid classes and 13 C enrichment of phospholipid fatty acids were measured and tracer oxidation was monitored. Compared with the control group, the MCT group showed lower breath 13 CO 2 and higher plasma triacylglycerol contents of octanoic acid, of decanoic acid, and of total long-chain polyunsaturated fatty acids (57.1 ؎ 4.4 mol/l vs. 37.9 ؎ 4.8 mol/l, P Ͻ 0.01). Concentrations of several polyunsaturated fatty acids in plasma phospholipids and non esterified fatty acids were higher in the MCT group. 13 C concentrations in phospholipid n-6 fatty acids indicated no difference in the relative conversion of linoleic to arachidonic acid. We conclude that oral MCT effectively reduce polyunsaturated fatty acid and long chain polyunsaturated fatty acid oxidation in preterm infants without compromising endogenous n-6 long chain polyunsaturated fatty acid synthesis.

DHA supply dose dependently increased plasma DHA. Formula DHA levels of 0.33% matched plasma DHA status of infants fed HM. LC-PUFA synthesis was lower in infants fed HM than formulas with different DHA and low AA contents. With the LC-PUFA supplementation used, DHA in formulas did not inhibit AA or DHA synthesis.

For years, brown tumors have been considered to be a characteristic of primary hyperparathyroidism. However, since 1963 several reports indicate the incidence of brown tumors in patients with renal secondary hyperparathyroidism to be 1.5%-1.7%. The appearance of multiple brown tumor lesions is rather uncommon in secondary hyperparathyroidism which is also true for malabsorption as its cause. We report on a 56-year-old man presenting with pain in the bones and multiple osteolyses. A bone biopsy specimen and the laboratory examinations were indicative of secondary hyperparathyroidism caused by malabsorption most likely due to Billroth's II/I gastric resection. Thus, the patient's osteolyses represent brown tumors which have been induced by nutritional secondary hyperparathyroidism.