Showing papers by "Gaby Palmer published in 2006"

Is IL-1 a good therapeutic target in the treatment of arthritis?

Abstract: Inflammation is an important homeostatic mechanism that limits the effects of infectious agents. However, inflammation might be self-damaging and therefore has to be tightly controlled or even abolished by the organism. Interleukin 1 (IL-1) is a crucial mediator of the inflammatory response, playing an important part in the body's natural responses and the development of pathological conditions leading to chronic inflammation. While IL-1 production may be decreased or its effects limited by so-called anti-inflammatory cytokines, in vitro IL-1 inflammatory effects are inhibited and can be abolished by one particularly powerful inhibitor, IL-1 receptor antagonist (IL-1Ra). Recent research has shown that in the processes of rheumatoid arthritis (RA) IL-1 is one of the pivotal cytokines in initiating disease, and IL-1Ra has been shown conclusively to block its effects. In laboratory and animal studies the inhibition of IL-1 by either antibodies to IL-1 or IL-1Ra proved beneficial to the outcome. Because of its beneficial effects in many animal disease models, IL-1Ra has been used as a therapeutic agent in human patients. The recombinant form of IL-1Ra, anakinra (Kineret, Amgen) failed to show beneficial effects in septic shock and displays weak effects in RA patients. However, IL-1 blockade by anakinra is dramatically effective in systemic-onset juvenile idiopathic arthritis, in adult Still's disease and in several autoinflammatory disorders, most of the latter being caused by mutations of proteins controlling IL-1beta secretion. Importantly, to be efficacious, anakinra required daily injections, suggesting that administered IL-1Ra displays very short-term effects. Better IL-1 antagonists are in the process of being developed.

The new IL-1 family member IL-1F8 stimulates production of inflammatory mediators by synovial fibroblasts and articular chondrocytes.

Abstract: Six novel members of the IL-1 family of cytokines were recently identified, primarily through the use of DNA database searches for IL-1 homologues, and were named IL-1F5 to IL-1F10. In the present study, we investigated the effect of IL-1F8 on primary human joint cells, and examined the expression of the new IL-1 family members in human and mouse joints. Human synovial fibroblasts (hSFs) and human articular chondrocytes (hACs) expressed the IL-1F8 receptor (IL-1Rrp2) and produced pro-inflammatory mediators in response to recombinant IL-1F8. IL-1F8 mRNA expression was increased in hSFs upon stimulation with proinflammatory cytokines, whereas in hACs IL-1F8 mRNA expression was constitutive. However, IL-1F8 protein was undetectable in hSF and hAC culture supernatants. Furthermore, although IL-1β protein levels were increased in inflamed human and mouse joint tissue, IL-1F8 protein levels were not. IL-1F8 levels in synovial fluids were similar to or lower than those in matched serum samples, suggesting that the joint itself is not a major source of IL-1F8. Serum levels of IL-1F8 were similar in healthy donors, and patients with rheumatoid arthritis, osteoarthritis and septic shock, and did not correlate with inflammatory status. Interestingly however, we observed high IL-1F8 levels in several serum samples in all groups. In conclusion, IL-1F8 exerts proinflammatory effects in primary human joint cells. Joint and serum IL-1F8 protein levels did not correlate with inflammation, but they were high in some human serum samples tested, including samples from patients with rheumatoid arthritis. It remains to be determined whether circulating IL-1F8 can contribute to joint inflammation in rheumatoid arthritis.

The role of leptin in innate and adaptive immune responses.

Abstract: Leptin is produced primarily by adipocytes and functions in a feedback loop regulating body weight. Leptin deficiency results in severe obesity and a variety of endocrine abnormalities in animals and humans. Several studies indicated that leptin plays an important role in immune responses. It exerts protective anti-inflammatory effects in models of acute inflammation and during activation of innate immune responses. In contrast, leptin stimulates T lymphocyte responses, thus having rather a proinflammatory role in experimental models of autoimmune diseases. Clinical studies have so far yielded inconsistent results, suggesting a rather complex role for leptin in immune-mediated inflammatory conditions in humans.

Indirect Effects of Leptin Receptor Deficiency on Lymphocyte Populations and Immune Response in db/db Mice

Abstract: Leptin-deficient ob/ob and leptin receptor (Ob-rb)-deficient db/db mice display a marked thymic atrophy and exhibit defective immune responses. Lymphocytes express leptin receptors and leptin exerts direct effects on T cells in vitro. In addition, ob/ob and db/db mice display multiple neuroendocrine and metabolic defects, through which leptin deficiency may indirectly affect the immune system in vivo. To study the relative contributions of direct and indirect effects of leptin on the immune system in a normal environment, we generated bone marrow chimeras (BMCs) by transplantation of leptin receptor-deficient db/db, or control db/+, bone marrow cells into wild-type (WT) recipients. The size and cellularity of the thymus, as well as cellular and humoral immune responses, were similar in db/db to WT and db/+ to WT BMCs. The immune phenotype of db/db mice is thus not explained by a cell autonomous defect of db/db lymphocytes. Conversely, thymus weight and cell number were decreased in the reverse graft setting in WT to db/db BMCs, indicating that expression of the leptin receptor in the environment is important for T cell development. Finally, normal thymocyte development occurred in fetal db/db thymi transplanted into WT hosts, indicating that direct effects of leptin are not required locally in the thymic microenvironment. In conclusion, direct effects of leptin on bone marrow-derived cells and on thymic stromal cells are not necessary for T lymphocyte maturation in normal mice. In contrast, leptin receptor deficiency affects the immune system indirectly via changes in the systemic environment.

The active metabolite of leflunomide, A77 1726, increases proliferation of human synovial fibroblasts in presence of IL-1beta and TNF-alpha.

Abstract: Excessive synovial fibroblast (SF) proliferation is detrimental in rheumatoid arthritis. We therefore sought to determine the effects of A77 1726, the active metabolite of leflunomide, on SF proliferation. Human SFs were used. Cell proliferation was investigated using MTS assay, by 3H-thymidine incorporation and cell counts. Whereas A77 1726 alone had no effects, it significantly increased the mitogenic effects of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Cyclooxygenase inhibition might be at least partly involved, since indomethacin displayed similar effects, and since prostaglandin E2 inhibited SF proliferation. In contrast, the effect of A77 1726 did not appear to be mediated through depletion of the pyrimidine pool or inhibition of tyrosine kinases. A77 1726 displays proliferative effects in presence of IL-1β and TNF-α. Further elucidation of involved mechanisms may prove useful for the utilization of leflunomide, the development of related compounds or elaboration of new therapeutic strategies.

Review The role of leptin in innate and adaptive immune responses

Abstract: Leptin is produced primarily by adipocytes and functions in a feedback loop regulating body weight. Leptin deficiency results in severe obesity and a variety of endocrine abnormalities in animals and humans. Several studies indicated that leptin plays an important role in immune responses. It exerts protective anti-inflammatory effects in models of acute inflammation and during activation of innate immune responses. In contrast, leptin stimulates T lymphocyte responses, thus having rather a proinflammatory role in experimental models of autoimmune diseases. Clinical studies have so far yielded inconsistent results, suggesting a rather complex role for leptin in immune-mediated inflammatory conditions in humans.