Adipocyte cell number is a crucial factor for controlling of body weight and metabolic function. The regulation of adipocyte numbers in the adult organism is not fully understood but is considered to depend on the homeostasis of cell differentiation and apoptosis. Herein, we show that targeted deletion of the activator protein (AP-1)-related transcription factor Fra-2 in adipocytes in vivo (Fra-2Dadip mice) induces a high-turnover phenotype with increased differentiation and apoptosis of adipocytes, leading to a decrease in body weight and fat pad mass. Importantly, adipocyte cell numbers were significantly reduced in Fra-2 Dadip mice. At the molecular level, Fra-2 directly binds to the PPARc2 promoter and represses PPARc2 expression. Deletion of Fra-2 leads to increased PPARc2 expression and adipocyte differentiation as well as increased adipocyte apoptosis through upregulation of hypoxia-inducible factors (HIFs). These findings suggest that Fra-2 is an important checkpoint to control adipocyte turnover. Therefore, inhibition of Fra-2 may emerge as a useful strategy to increase adipocyte turnover and to reduce adipocyte numbers and fat mass in the body.

The role of AP-1 transcription factors in early B cell development and function is still incompletely characterized. Ubieta at al. describe the function of the Fra-2/AP-1 transcription factor as a regulator of Foxo1 and Irf4 expression in B cells. Fra-2 affects B cell proliferation and maintains their number in bone marrow.

In teleosts fish, secretion of GH is regulated by several hypothalamic factors that are influenced by the physiological state of the animal. There is an interaction between immune and endocrine systems through hormones and cytokines. GH in fish is involved in many physiological processes that are not overtly growth related, such as saltwater osmoregulation, antifreeze synthesis, and the regulation of sexual maturation and immune functions. This study was conducted to characterize a decapeptide compound A233 (GKFDLSPEHQ) designed by molecular modeling to evaluate its function as a GH secretagogue (GHS). In pituitary cell culture, the peptide A233 induces GH secretion and it is also able to increase superoxide production in tilapia head-kidney leukocyte cultures. This effect is blocked by preincubation with the GHS receptor antagonist [D-Lys 3 ]-GHRP6. Immunoneutralization of GH by addition of anti-tilapia GH monoclonal antibody blocked the stimulatory effect of A233 on superoxide production. These experiments propose a GH-mediated mechanism for the action of A233. The in vivo biological action of the decapeptide was also demonstrated for growth stimulation in goldfish and tilapia larvae (P!0 . 001). Superoxide dismutase levels, antiprotease activity, and lectin titer were enhanced in tilapia larvae treated with this novel molecule. The decapeptide A233 designed by molecular modeling is able to function as a GHS in teleosts and enhance parameters of the innate immune system in the fish larvae.

Background T cells are important regulators of inflammation and, via release of mediators, can contribute to pulmonary fibrosis. Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease (ILD) and chronic fibrosing ILDs with a progressive phenotype. However, how nintedanib targets T cells has not been elucidated. Materials and Methods We investigated the immunomodulatory effects of nintedanib on T cells and peripheral blood mononuclear cells isolated from healthy donors. Cells were pre-incubated with different concentrations of nintedanib and then stimulated for 24 hours with anti-CD3 with or without anti-CD28 and with or without different cytokines. Levels of interferon gamma (IFN-γ), interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12p70 and IL-13 were quantitated. Western blotting with primary antibodies against phospho-Lck-Y394, phospho-Lck-Y505, Lck-total and Cofilin examined the phosphorylation level of the Lck protein. In vitro T-cell proliferation, T-cell clustering and different T-cell populations were also assessed. Results Nintedanib blocked T-cell activation through inhibiting Lck-Y394 phosphorylation. Pretreatment of T cells with nintedanib reduced cluster formation as a marker of activation and inhibited the release of IFN-γ, IL-2, IL-4, IL-5, IL-10, IL-12p70 and IL-13 at clinically relevant concentrations ranging from 5–77 nmol/L. Nintedanib did not alter T-cell proliferation or numbers of CD4+ and CD8+ T cells, but did increase stimulated Th17-like cells without increasing IL-17A levels. Conclusion These immunomodulatory effects may further explain how nintedanib slows the progression of pulmonary fibrosis in various ILDs.

Objective. To determine whether overexpression of the activator protein 1 (AP-1) transcription factor Fra-1 in adipose-derived stromal cells (ADSCs) is an effective treatment of collagenase-induced osteoarthritis (OA).Methods. OA was induced by injection of collagenase into the knee joints of male C57BL/6 mice. ADSCs were isolated from the inguinal fat pads of 8-week-old wild-type or Fra-1-transgenic mice and injected into the knee joints of mice with collagenase-induced OA 7 days after OA induction. Histologic analyses of cartilage destruction and chondrocyte cell death were performed. Adipogenic differentiation capacity was evaluated, gene expression was analyzed, and cytokine profiling was performed in stromal vascular fractions (SVFs) and ADSCs.Results. OA-related cartilage destruction and chondrocyte cell death were significantly reduced in mouse knee joints treated with ADSCs from Fra-1-transgenic mice compared to mouse knee joints treated with ADSCs from wild-type mice. This effect did not result from the higher number of adipogenic progenitors observed in SVFs from Fra-1-transgenic compared to wild-type mouse fat pads, since injection of wild-type mouse ADSCs enriched for adipogenic progenitors did not show any additional chondroprotective effects compared to nonsorted ADSCs. However, Fra-1-transgenic mouse ADSCs showed decreased adipogenic differentiation capacity. Moreover, Fra-1 significantly inhibited proinflammatory interleukin-6 and pentraxin 3 expression, while increasing the expression of extracellular matrix proteins, such as periostin and spondin 1. These findings suggest that Fra-1 overexpression leads to an increased chondroprotective effect of ADSCs in OA.Conclusion. ADSCs overexpressing Fra-1 effectively protect against OA. Our data indicate that genetic modifications of ADSCs, such as Fra-1 overexpression, may improve their potential to protect articular cartilage against OA-mediated damage.Osteoarthritis (OA) is the most common rheumatic disease, characterized by degeneration of articular cartilage. OA patients experience intense pain and impaired physical function. The high prevalence of OA, along with the severe disease burden, is also associated with high socioeconomic costs and loss of productivity (1,2). Mechanistically, it is thought that the balance between anabolic and catabolic factors in cartilage is disturbed, leading to a catabolic phenotype of articular chondrocytes. Different primary triggers eventually lead to a decrease in the capacity of chondrocytes to secrete specific components of the extracellular matrix, such as type IIB collagen or aggrecan, while at the same time the synthesis of catabolic enzymes, such as aggrecanases of the ADAMTS family and collagenases of the matrix