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OBJECTIVE: Caspase 1, a known cysteine protease, is a critical component of the inflammasome. Both caspase 1 and neutrophil serine proteases such as proteinase 3 (PR3) can process pro-interleukin-1beta (proIL-1beta), a crucial cytokine linked to the pathogenesis of rheumatoid arthritis. This study was undertaken to establish the relative importance of caspase 1 and serine proteases in mouse models of acute and chronic inflammatory arthritis. METHODS: Acute and chronic arthritis were induced in caspase 1(-/-) mice, and the lack of caspase 1 was investigated for its effects on joint swelling, cartilage metabolism, and histopathologic features. In addition, caspase 1 activity was inhibited in mice lacking active cysteine proteases, and the effects of dual blockade of caspase 1 and serine proteases on arthritis severity and histopathologic features were evaluated. RESULTS: Surprisingly, caspase 1(-/-) mice, in a model of acute (neutrophil-dominated) arthritis, developed joint swelling to an extent similar to that in wild-type control mice. Joint fluid concentrations of bioactive IL-1beta were comparable in caspase 1(-/-) mice and controls. In contrast, induction of chronic arthritis (characterized by minimal numbers of neutrophils) in caspase 1(-/-) mice led to reduced joint inflammation and less cartilage damage, implying a caspase 1-dependent role in this process. In mice lacking neutrophil serine PR3, inhibition of caspase 1 activity resulted in decreased bioactive IL-1beta concentrations in the synovial tissue and less suppression of chondrocyte anabolic function. In addition, dual blockade of both PR3 and caspase 1 led to protection against cartilage and bone destruction. CONCLUSION: Caspase 1 deficiency does not affect neutrophil-dominated joint inflammation, whereas in chronic arthritis, the lack of caspase 1 results in reduced joint inflammation and cartilage destruction. These findings suggest that inhibitors of caspase 1 are not able to interfere with the whole spectrum of IL-1beta production, and therefore such inhibitors may be of therapeutic value only in inflammatory conditions in which limited numbers of neutrophils are present. [ABSTRACT FROM AUTHOR]

Background Adipokines are involved in the regulation of many inflammatory processes and are present at very high concentrations in cord blood of term infants. Objective We analysed data of a large prospective birth cohort study to examine whether adiponectin and leptin concentration in cord blood are determinants of wheezing disorders in children within the first 2 years of life. Methods Seven hundred and forty mothers and their newborns were included in this analysis. Adiponectin and leptin concentrations were measured in cord blood. The cumulative incidence of physician-reported asthma or obstructive bronchitis was recorded during a 2-year follow-up. Results During the first 2 years of life, asthma or obstructive bronchitis was reported by the caring paediatricians for 157 (19.6%) of the children. We found a strong interaction of cord blood adiponectin and history of atopic disease in the mother with respect to the risk of physician-reported asthma or obstructive bronchitis ( P=0.006). Compared with children with cord blood levels in the middle quintile (reference category), the odds ratios for physician-reported asthma or obstructive bronchitis in the bottom quintile and top quintile were 0.14 [95% confidence interval (CI) 0.02–0.90] and 2.12 (95% CI 0.67–6.66), respectively ( P for trend=0.0003), among children of mothers with a history of atopy. This association was independent of other established risk factors. Leptin levels in cord blood were not associated with risk of asthma or obstructive bronchitis. Conclusions In children of mothers with a history of atopy, concentrations of adiponectin in cord blood could play an important role in determining risk of wheezing disorders in early childhood. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The roles of the transmembrane and secreted forms of tumor necrosis factor alpha (TNFalpha) in rheumatoid arthritis (RA) remain unclear. Agents used to inhibit TNFalpha have shown varying efficacy in RA patients, suggesting that anti-TNFalpha agents possess dissimilar mechanisms of action, including the ability to neutralize transmembrane (tmTNFalpha) and secreted TNFalpha. In this study, TNFalpha-knockout (TNFalpha-KO) mice that were genetically altered to express elevated levels of tmTNFalpha were constructed to further understand the roles of the 17-kd secreted, trimeric, and 26-kd transmembrane forms of TNFalpha. METHODS: A speed-congenic mating scheme was used to generate 3 unique strains of mice: 1) transgenic tmTgA86 mice overexpressing 26-kd tmTNFalpha and also secreting 17-kd trimeric TNFalpha (tmTNFalpha-transgenic), 2) TNFalpha(-/-) mice (TNFalpha-KO), and 3) transgenic mice overexpressing tmTNFalpha backcrossed to TNFalpha-KO mice (tmTNFalpha-transgenic/TNFalpha-KO). Mice were treated with phosphate buffered saline (as vehicle control), dexamethasone (as positive control), or modified recombinant human soluble TNF receptor (sTNFR) p55 or p75, and were assessed clinically and histopathologically for signs of inflammation and development of arthritis. RESULTS: The tmTNFalpha-transgenic/TNFalpha-KO mice were born with crinkled tails and spinal deformities similar to those in ankylosing spondylitis. By 2-4 weeks, these mice developed symmetric inflammatory arthritis, characterized by tissue swelling, pannus formation, and bone deformities. The tmTNFalpha-transgenic mice also developed spontaneous-onset arthritis, but at a slower rate (100% incidence by 10-12 weeks). Clinical and histologic progression of arthritis in the tmTNFalpha-transgenic/TNFalpha-KO mice was reduced by treatment with dexamethasone or with the p55 or p75 sTNFR (69% and 63% reduction in total histologic score, respectively). CONCLUSION: These data show that arthritis is sufficiently initiated and maintained in tmTNFalpha-transgenic/TNFalpha-KO mice, and that it can be neutralized by recombinant human p55 or p75 sTNFR, resulting in amelioration of the biologic and subsequent histologic destructive effects of tmTNFalpha. [ABSTRACT FROM AUTHOR]

The study of cytokine-deficient mice has provided important information for a better understanding of inflammatory processes. In this report, the characterization of mice deficient for various components of the interleukin (IL)-1 system is reviewed. Results obtained by studying mice deficient for IL-1α, IL-1β, IL-1 receptor antagonist, IL-1 receptor type I, IL-1 receptor accessory protein, IL-1 receptor-associated kinase, and the IL-1β-converting enzyme caspase-1 are summarized. Because some of the components of the IL-1 system are shared with IL-18, similarities between IL-1β and IL-18 are also discussed. [ABSTRACT FROM AUTHOR]

We have previously shown that chlorpromazine (CPZ) inhibits tumour necrosis factor (TNF) production and protects against endotoxic shock in mice. In this paper we investigated the effect of pretreatment with CPZ, 4 mg/kg i.p. 30 min before, compared with dexamethasone (DEX; 3 mg/ kg) on the induction of other endotoxin (lipopolysaccharide; LPS)-induced cytokines in the serum of mice, i.e. interleukin-lα (IL-lα), IL-6 and IL-b, and TNF. We also studied the effect of CPZ on serum and spleen-associated TNF. Both DEX and CPZ inhibited TNF production, whereas induction of IL-b and IL-6 was inhibited by DEX but not by CPZ. DEX did not affect IL-l0, while CPZ potentiated its induction. CPZ also inhibited spleen-associated TNF induction in LPS- treated mice, suggesting an effect on the synthesis of TNF. CPZ inhibited TNF induction by Gram-positive bacteria (heat-killed Staphylococcus epidermidis) and by anti-CD3 monoclonal antibodies. Intraperitoneal administration of CPZ also inhibited the induction of brain-associated TNF induced by intra-cerebroventricular injection of LPS. Therefore, CPZ is a more specific inhibitor of TNF production than DEX; in particular, CPZ increased the induction of 1L-l0, which is a `protective' cytokine known to inhibit LPS toxicity and TNF production. CPZ inhibited TNF production in vivo, irrespective of the TNF stimulus used to induce TNF. Finally, CPZ did not induce the `rebound' effect of DEX that, when given 24 hr before LPS, potentiates TNF production, but it did inhibit TNF production after 24 hr. [ABSTRACT FROM AUTHOR]

Chlorpromazine (CPZ) has been previously shown to protect against endotoxin [lipopolysacchar- ide (LPS)] lethality and inhibit the release of tumour necrosis factor in vivo. We investigated at the cellular level whether this was due to direct inhibition of tumour necrosis factor-α (TNF-α) synthesis, using LPS-stimulated THP-1 human monocytic leukemia cells. We also studied the effect of CPZ on human TNF-α action by assessing TNF-α cytotoxicity on mouse fibrosarcoma L929 cells. CPZ (1–100 μM) inhibited TNF-α production in THP-1 cells in a dose dependent manner by a maximum of 80%. This effect was comparable to that of two well-known inhibitory drugs, dexamethasone and cyclicAMP. Inhibition was also evident at the mRNA level. On the other hand CPZ (10–25 μM) also inhibited TNF-α activity: in fact it reduced the cytotoxicity of TNF-α on L929 cells (EC50 was increased four times) and could provide protection even as a post- treatment. CPZ inhibited TNF-induced apoptosis in L929 cells, as detected by analysis of nuclear morphology. However, since we showed that apoptosis was very limited, and was not the main mode of cell death in our conditions, this could not explain the overall protection. Since CPZ did not interfere with either the oligomerization state of TNF-α or its receptor binding, our data suggest that it reduced cytotoxicity by inhibiting some steps in the TNF-α signalling pathways. [ABSTRACT FROM AUTHOR]

Background: Primary Prevention of Diabetes Program in Buenos Aires Province evaluates the effectiveness of adopting healthy lifestyle to prevent type 2 diabetes (T2D) in people at high risk of developing it. We aimed to present preliminary data analysis of FINDRISC and laboratory measurements taken during recruitment of people for the Primary Prevention of Diabetes Program in Buenos Aires Province in the cities of La Plata, Berisso, and Ensenada, Argentina., Methods: People were recruited through population approach (house-to-house survey by FINDRISC in randomized areas) and opportunistic approach (FINDRISC completed by participants during consultations for nonrelated prediabetes/diabetes symptoms in public and private primary care centres of cities involved). In people with FINDRISC score ≥ 13 points, we evaluated blood concentrations of HbA 1c , creatinine, lipids, and an oral glucose tolerance test (OGTT)., Results: Approximately 3415 individuals completed the FINDRISC populational survey and 344 the opportunistic survey; 43% of the 2 groups scored over 13 points; 2.8 and 75.4% of them, respectively, took the prescribed OGTT. Approximately 53.7% of the OGTT showed normal values and 5.2% unknown T2D. The remaining cases showed 69.5% impaired fasting glucose, 13.6% impaired glucose tolerance, and 16.9% both impairments. HbA 1c values showed significant differences compared with normal glucose tolerance (4.96 ± 0.43%), prediabetes (5.28 ± 0.51%), and T2D (5.60 ± 0.51%). Participants with prediabetes and T2D showed a predominant increase in low-density lipoprotein-cholesterol values. In prediabetes, >50% showed insulin resistance., Conclusions: People with prediabetes/T2D had dyslipidemia associated with insulin resistance, which promotes the development of T2D and cardiovascular disease. Thus, it merits its appropriate treatment., (Copyright © 2017 John Wiley & Sons, Ltd.)