Background: Rheumatoid arthritis is a chronic autoimmune inflammatory condition characterised by polyarthritis and severe change in body mass and neuroendocrine environment. Objectives: To investigate plasma levels of adipocytokines (leptin, adiponectin, visfatin and resistin) in patients with rheumatoid arthritis and to compare them with levels in healthy controls. Methods: Adiponectin, resistin, visfatin and leptin concentrations were measured in 31 patients with rheumatoid arthritis and 18 healthy controls by using specific enzyme-linked immunosorbent assays. Results: Patients with rheumatoid arthritis showed considerably higher plasma levels of leptin, adiponectin and visfatin than healthy controls. No marked difference was observed in resistin levels between patients and controls. Conclusion: A marked increase in plasma levels of leptin, adiponectin and visfatin was noted in patients with rheumatoid arthritis, whereas resistin levels were similar to those observed in healthy controls. Coordinated roles for adiponectin, leptin and visfatin are suggested in the modulation of the inflammatory environment in patients with rheumatoid arthritis, whereas the lack of modulation in resistin levels is predictive of an irrelevant role for this peptide, suggesting that resistin level is probably not one of the main signals associated with the pathogenesis of this disease.

Leptin is 16 kDa adipokine that links nutritional status with neuroendocrine and immune functions. Initially thought to be a satiety factor that regulates body weight by inhibiting food intake and stimulating energy expenditure, leptin is a pleiotropic hormone whose multiple effects include regulation of endocrine function, reproduction, and immunity. Leptin can be considered as a pro-inflammatory cytokine that belongs to the family of long-chain helical cytokines and has structural similarity with interleukin-6, prolactin, growth hormone, IL-12, IL-15, granulocyte colony-stimulating factor and oncostatin M. Because of its dual nature as a hormone and cytokine, leptin links the neuroendocrine and the immune system. The role of leptin in the modulation of immune response and inflammation has recently become increasingly evident. The increase in leptin production that occurs during infection and inflammation strongly suggests that leptin is a part of the cytokine network which governs the inflammatory-immune response and the host defense mechanisms. Leptin plays an important role in inflammatory processes involving T cells and has been reported to modulate T-helper cells activity in the cellular immune response. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions, such as experimental autoimmune encephalomyelitis, type 1 diabetes, rheumatoid arthritis, and intestinal inflammation. Very recently, a key role for leptin in osteoarthritis has been demonstrated: leptin indeed exhibits, in concert with other pro-inflammatory cytokines, a detrimental effect on articular cartilage by promoting nitric oxide synthesis in chondrocytes. Here, we review the recent advances regarding leptin biology with a special focus on those actions relevant to the role of leptin in the pathophysiology of inflammatory processes and immune responses.

These results bind more closely the interactions between fat-derived adipokines and articular inflammatory diseases, and suggest that adiponectin is a novel key element in the maintenance of cartilage homeostasis which might be considered as a potential therapeutical target in joint degenerative diseases.

Leptin is a 16 kDa adipocyte-secreted hormone that regulates weight centrally and links nutritional status with neuroendocrine and immune function. Since its cloning in 1994, leptin's role in regulating immune and inflammatory response has become increasingly evident. Actually, the increase of leptin production that occurs during infection and inflammation strongly suggests that leptin is a part of the cytokines loop which governs the inflammatory-immune response and the host defence mechanism. Indeed, leptin stimulates the production of pro-inflammatory cytokines from cultured monocytes and enhances the production of Th1 type cytokines from stimulated lymphocytes. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions such as type 1 diabetes, rheumatoid arthritis and chronic bowel disease. Obesity is characterized by elevated circulating leptin levels which might contribute significantly to the so called low-grade systemic inflammation, making obese individuals more susceptible to the increased risk of developing cardiovascular diseases, type II diabetes or inflammatory articular degenerative disease such as osteorathritis (OA). As a matter of fact, a key role for leptin in OA has been recently demonstrated since leptin exhibits, in synergy with other pro-inflammatory cytokines, a detrimental effect on articular cartilage cells by promoting nitric oxide synthesis. This review will focus prevalently on the complex relationships existing among leptin, inflammatory response and immunity, trying to provide surprising insights into leptin's role and to discuss challenges and prospects for the future.

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Initially described as a satiety factor with neuroendocrine properties, leptin has been shown to regulate immune and inflammatory processes. Mainly produced by white adipose tissue, this hormone was first known to regulate energy homeostasis by inhibiting food intake and by upregulating energy consumption. Leptin is a dual molecule: apart from its actions as a hormone involved in energy homeostasis, increasing evidence suggests that leptin is a novel proinflammatory adipocyte-derived factor that operates in the cytokine network by linking immune and inflammatory processes to the neuroendocrine system. In fact, recent findings have shown that leptin regulates and participates both in immune homeostasis and inflammatory processes not only by acting as a modulator of T-cell activity, but also by playing a key role in a host of autoimmune inflammatory conditions such as autoimmune encephalomyelitis, type 1 diabetes, bowel inflammation and articular degenerative diseases such as osteoarthritis and rheumatoid arthritis. This review will more closely address leptin's cytokine properties rather than its role as a metabolic hormone by focusing on its biological actions in inflammatory processes, specifically those related to degenerative inflammatory diseases of the joints.

The objective of the present study was to investigate the effect of leptin, alone or in combination with IL-1, on nitric oxide synthase (NOS) type II activity in vitro in human primary chondrocytes, in the mouse chondrogenic ATDC5 cell line, and in mature and hypertrophic ATDC5 differentiated chondrocytes. For completeness, we also investigated the signalling pathway of the putative synergism between leptin and IL-1. For this purpose, nitric oxide production was evaluated using the Griess colorimetric reaction in culture medium of cells stimulated over 48 hours with leptin (800 nmol/l) and IL-1 (0.025 ng/ml), alone or combined. Specific pharmacological inhibitors of NOS type II (aminoguanidine [1 mmol/l]), janus kinase (JAK)2 (tyrphostin AG490 and Tkip), phosphatidylinositol 3-kinase (PI3K; wortmannin [1, 2.5, 5 and 10 µmol/l] and LY294002 [1, 2.5, 5 and 10 µmol/l]), mitogen-activated protein kinase kinase (MEK)1 (PD098059 [1, 5, 10, 20 and 30 µmol/l]) and p38 kinase (SB203580 [1, 5, 10, 20 and 30 µmol/l]) were added 1 hour before stimulation. Nitric oxide synthase type II mRNA expression in ATDC5 chondrocytes was investigated by realtime PCR and NOS II protein expression was analyzed by western blot. Our results indicate that stimulation of chondrocytes with IL-1 results in dose-dependent nitric oxide production. In contrast, leptin alone was unable to induce nitric oxide production or expression of NOS type II mRNA or its protein. However, co-stimulation with leptin and IL-1 resulted in a net increase in nitric oxide concentration over IL-1 challenge that was eliminated by pretreatment with the NOS II specific inhibitor aminoguanidine. Pretreatment with tyrphostin AG490 and Tkip (a SOCS-1 mimetic peptide that inhibits JAK2) blocked nitric oxide production induced by leptin/IL-1. Finally, wortmannin, LY294002, PD098059 and SB203580 significantly decreased nitric oxide production. These findings were confirmed in mature and hypertrophic ATDC5 chondrocytes, and in human primary chondrocytes. This study indicates that leptin plays a proinflammatory role, in synergy with IL-1, by inducing NOS type II through a signalling pathway that involves JAK2, PI3K, MEK-1 and p38 kinase.

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