Objective. To test the hypothesis that nitric oxide (NO) is involved in the pathophysiology of arthritis.Methods. Arthritis was induced in male Lewis rats by the injection of adjuvant into the base of the tail. The NO synthase (NOS) inhibitor, NG-monomethyl-Larginine (L-NMA), was administered daily by the oral route for 19 days. Paw swelling, plasma fibrinogen levels, and urinary NOJNO, levels were measured to assess the effect of L-NMA on the arthritic response and whole-body NO production, respectively. On day 20, the ankle joints were processed for histopathologic evaluation.Results. The onset of clinical symptoms was preceded by elevated biosynthesis of NO. In a dosedependent manner, L-NMA inhibited both NO biosynthesis and paw swelling; histopathologic changes in the ankle joints were also prevented. D-NMA had no effect on the development of arthritis, while L-arginine reversed the effects of L-NMA. Fibrinogen levels in rats with arthritis were unaffected by L-NMA.Conclusion. NO is critical to the development of both the inflammatory and erosive components of adjuvant arthritis in rats. There may be a future clinical role for suitable inhibitors of NO production or activity.Rheumatoid arthritis is a chronic, incurable disease characterized by joint swelling, synovial in- flammation, and cartilage destruction. Antagonism of the mediators which drive these pathophysiologic changes represents one approach to improving the treatment of this condition. Such an endeavor requires the prior identification of the appropriate mediators. In a recent review (I), it was suggested that nitric oxide (NO) should be investigated in this regard; the present paper reports the results of a study that was designed to do so.In vitro studies have demonstrated that both the resident mesenchymal cells of the joints and the leukocytes which enter joints during inflammation have the capacity to synthesize considerable amounts of NO. Thus, cultures of articular chondrocytes (2,3) and synoviocytes (4) produce high levels of NO following activation by interleukin-1, a cytokine present in rheumatoid synovial fluids. Macrophages (9, polymorphonuclear leukocytes (6), mast cells (7), and, possibly, lymphocytes (8) are additional potential sources of NO in inflamed joints. Analysis of synovial fluids (9,lO) from arthritic joints has confirmed the presence of elevated amounts of nitrate and nitrite, the stable end products to which NO spontaneously oxidizes in vivo. Previous animal studies have implicated NO in inflammation (1 I), immunity (12), and tissue destruction (13).NO is synthesized by the enzyme NO synthase (NOS), which exists as several isozymes (14), the main distinction being between constitutive (cNOS) and inducible (iNOS) forms. Cells that contain cNOS quickly and transiently produce small amounts of NO in response to agonists which raise intracellular Ca2' concentrations, while cells with iNOS produce large amounts of NO for a prolonged period following a lag of several hours during which the enzyme is induced.Chondrocytes (2),...

No abstract

No abstract

No abstract

This review focuses on research findings that provide insight into the contribution of PGE2 and IL-23 during the development of pathogenic Th17 cells. We also highlight the key transcriptional factors required for Th17 development and therapeutic strategies to disrupt the interaction between IL-23 and IL-17 to prevent the end-organ damage in RA.

Lipocalin-2 (Lcn2) is an innate immune protein elevated by several orders of magnitude in various inflammatory conditions including aging and obesity. Recent studies have shown that Lcn2 is secreted by adipocytes in response to inflammation and is categorized as a new adipokine cross-linking innate immunity and metabolic disorders including obesity. However, the involvement of Lcn2 and its function during the progression of obesity is largely unknown. Recently, browning of white adipose tissue (WAT) has gained attention as a therapeutic strategy to combat obesity. Herein, we have shown that treatment of mature 3T3-L1 adipocytes with recombinant Lcn2 (rec-Lcn2) resulted in the up-regulation of thermogenic and beige/brown markers (UCP1, PRDM16, ZIC-1 and TBX1) and increased mitochondrial activity. Additionally, global Lcn2 genetic knockout (Lcn2KO) mice exhibited accelerated weight gain and visceral fat deposition with age, when compared to wild type (WT) mice. Taken together, both in vitro and in vivo studies suggest that Lcn2 is a naturally occurring adipokine, and may serve as an anti-obesity agent by upregulating the thermogenic markers resulting in the browning of WAT. Therefore, Lcn2 and its downstream signaling pathways could be a potential therapeutic target for obesity. Obesity is a chronic low-grade inflammatory disorder. With nearly 40% of the adult population in the United States being obese, it is no longer just a problem of uncontrolled weight gain but considered as a chronic disease of epidemic proportions. Obesity increases the risk of several disorders, including type-2 diabetes, cardiovascular disease, stroke and bone loss 1. The expense of treating obesity-related illnesses is also increasing and now accounts for nearly 28% of total health-care costs 2. It is estimated that obesity treatment costs between $147 and 210 billion per year, with another $4.3 billion in lost productivity 3-5. Despite the global burden of the disease, there are limited FDA approved anti-obesity drugs available and their use is tempered by significant adverse side effects 6-8. As obesity is now a national epidemic, there is a critical need for the development of anti-obesity drugs with fewer side effects. Adipose tissue plays a vital role in regulating the metabolic disorders and inflammation. White adipose tissue (WAT) primarily functions as an energy storage unit and is a source for inflammatory mediators 9-12. Dysfunction of WAT leads to progression of obesity and its related metabolic disorders 13. Recent studies have shown that conversion of WAT to brown-like beige adipose tissue, known as browning of WAT, is a promising target for the treatment of obesity and associated metabolic and inflammatory disorders 13. Browning of WAT, accompanied by increased mitochondrial activity and thermogenesis, has been reported to decrease weight gain in the high fat diet (HFD) fed obese mouse models 14. More recently, lipocalin 2 (Lcn2) is categorized as a new adipokine secreted by various cell types including adipocytes. It has al...

Lipocalin2 (Lcn2) belongs to a small molecular weight lipocalin subfamily of secretory proteins that binds to small hydrophobic molecules. Recent studies have shown that Lcn2 is highly upregulated by adipocytes and is categorized as a new adipokine with a role in innate immunity and metabolic disorders, including obesity. However, the exact role Lcn2 plays in the mediation and progression of obesity has yet to be elucidated. Herein, we have investigated the role of exogenous Lcn2 in inducing the browning of white adipocytes in vitro using the 3T3-L1 murine adipocyte cell line. Treatment with exogenous recombinant Lcn2 (rec-Lcn2) resulted in the upregulation of thermogenic and beige/brown markers (UCP1, PGC-1α, PPARγ, PRDM16, ZIC-1 and TBX1) in mature adipocytes. Additionally, rec-Lcn2 increased mitochondrial activity in 3T3-L1 cells. Further, rec-Lcn2 decreased the pre-adipocyte differentiation resulting in the attenuation of adipogenesis as evidenced by reduced lipid content accumulation. These results suggest that Lcn2 is a naturally occurring adipokine, and may serve as an anti-obesity agent by both decreasing adipogenesis in white adipocytes and inducing the transdifferentiation of white to brown-like beige adipocytes. Therefore, Lcn2 could be a potential target to attenuate/prevent obesity.

No abstract