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Cure Arthritis Naturally

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In addition to participating in some aspects of acute inflammation, prostaglandins of the E series and prostacyclin can suppress a number of chronic immunological responses. Systemic administration of PGE2 or its analogs can suppress disease activity in animal models of chronic inflammation such as adjuvant arthritis, immune colitis or glomerulonephritis. These actions have been attributed to effects on lymphocyte function, since prostaglandin E2 is a potent inhibitor of lymphocyte proliferation and can suppress the production of lymphokines from T cells.

Macrophage activation is also decreased in vitro in the presence of concentrations of PGE2 that can be detected at sites of inflammation. In particular, there are many reports that PGE2 can inhibit the pro duction of IL-1 and TNFa. These cytokines are found at sites of chronic inflammation and play a central role in the recruitment of neutrophils, macrophages and lymphocytes. Interleukin 1 and TNFa can also induce procoagulant activity on endothelial cells which leads to deposition of fibrin, a characteristic feature of chronic autoimmune reactions. Furthermore, these cytokines cause tissue damage by the induction and release of proteolytic enzymes from mesenchymal cells, which also respond by synthesizing prostaglandins. The prostaglandins so produced may act through a feedback mechanism to inhibit cytokine generation from macrophages. Prostaglandin E2 has been convincingly demonstrated to inhibit the production of mature TNFa protein activity and downregulate the level of mRNA for TNFa in macrophages. Whether PGE, inhibits IL-1 secretion is less certain, but since PGE2 inhibits T cell function, this could indirectly suppress IL-1 generation. These interactions between eicosanoids and cytokines are shown in Figure 2.

Since NSAIDs inhibit prostaglandin synthesis in inflamed tissues, treatment with these drugs may

T cell

T cell

Figure 2 A proposed scheme to demonstrate the interaction between T lymphocytes and macrophages that can lead to cytokine production which, in turn, initiate the processes of leukocyte infiltration, fibrin deposition and tissue damage. Prostaglandin E? is also produced during this interaction which can downregulate T cell and macrophage activation.

Figure 2 A proposed scheme to demonstrate the interaction between T lymphocytes and macrophages that can lead to cytokine production which, in turn, initiate the processes of leukocyte infiltration, fibrin deposition and tissue damage. Prostaglandin E? is also produced during this interaction which can downregulate T cell and macrophage activation.

enhance cytokine production and exacerbate some chronic aspects of autoimmune disease. Indeed, both indomethacin and ibuprofen have been shown to enhance TNFcx production in vivo which is likely to explain why these agents increase mortality in murine endotoxic shock and enhance cartilage degradation in rabbits with antigen-induced arthritis. These findings have obvious clinical implications for patients receiving NSAID therapy for the treatment of chronic inflammatory diseases. It is tempting to speculate that in diseases such as rheumatoid arthritis NSAIDs, while ameliorating the disease symptoms may exacerbate the underlying diseases process leading to enhanced bone and cartilage destruction. There have been several suggestions in the literature that NSAIDs may accelerate the radiological changes that occur in osteoarthritis but definitive proof is lacking because long-term trials with large numbers of patients comparing an NSAID with placebo have never been conducted since all patients require NSAID therapy to provide analgesia. However, there is clear clinical evidence that NSAIDs can exacerbate inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis. Such actions may reflect a reduction in the local biosynthesis of cytoprotective prostanoids in the intestinal mucosa. However, since increased cytokine production leading to fibrin deposition and multifocal infarction has been implicated in the pathogenesis of IBD, removal of immunosuppressive prostanoids may underly the exacerbation of colitis by NSAIDs.

Prostaglandin E2 can also inhibit the expression of major histocompatibility complex (MHC) class II molecules, and consequently can interfere with the presentation of antigen to T cells by macrophages. Although PGE2 and prostacyclin have potent effects on immunocompoetent cells, there is little evidence that other cyclo-oxygenase products, such as thromboxane, can effect lymphocyte or macrophage function.

In addition to suppressing T cell and macrophage function, prostaglandins in some circumstances can stimulate immune responsiveness. The production of immunoglobulin M (IgM) rheumatoid factors by human rheumatoid mononuclear cells is inhibited by indomethacin in vitro, an effect reversed by exogenous PGE2. These observations can be explained In inhibition of T suppressor cell activity by PGE2. In contrast to these findings, indomethacin has been shown to enhance humoral immunity in some animal models. Clearly, the site of production and the concentration of mediator produced is critical in determining whether prostaglandins have immunosuppressive or immunostimulatory effects.

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Arthritis Relief and Prevention

Arthritis Relief and Prevention

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