[img] Text

Download (18kB)


We have been investigation the roles of cyclooxygenase-1 and 2 (COX-1 and COX-2) on the induction of collagen-induced arthritis, an animal model of rheumatoid arthritis and have demonstrated that COX-2 gene ablation suppresses susceptibility to CIA. The inhibition of CIA in COX-2-/- mice was associated with pronounced reduction in the production of anti-CII antibodies compared to that in COX-1-/- and WT mice. CIA could not be passively transferred to COX-2-/- mice using anti-CII monoclonal antibodies, but could not be passively transferred to WT and COX-1-/-littermates. These observations indicated that there must be a factor other than a suppressed anti-CII humoral response inhibiting susceptibility to this autoimmune disease in COX-2-/- mice Therefore in order to examine the COX-2-/- phenotype with respect to suppression of autoimmune as well as systemic inflammatory responses we took the following approach. First we determined whether COX-2 deficiency alters the function of the immune system, due to a developmental defect in the production of lymphoid or myeloid cells, or impaired functions of lymphocytes and APC. Quantitative analysis of mononuclear cells in peripheral blood and lymphoid organs of WT and COX-null mice indicated no significant defect in the production of lympoid or myeloid cells in COX-2-/- mice to in vitro antigenic (CII) stimulation were comparable to WT cells. These observations suggest that the suppression of anti-CII humoral response in COX-2-/- mice is not caused by either a development defect of the immune system, or by a defect in the function of the recognition arm of the immune system. However our observations indicate a significant drop in the percentage of mature B cells and macrophages in tissues of COX-2-/- mice post-immunization. Previous studies have suggested an important role of p53 in promoting activation induced death of B cells and macrophages, as well as a role of COX-2 in counteracting p53-induced apoptosis. In view of these findings we propose that in the absence of COX-2 survival of B cells and macrophages post-immunization may be impaired, and this may be a factor suppressing the anti-CII humoral response as well as preventing an inflammatory response in the joints of COX-2-/- mice Second we considered the possibility of suppressed effecter functions of the immune systems in COX-2-/- mice, due to altered production of soluble mediators like cytokines and eicosanoids by COX-2-/- cells. Analysis of eicosanoids produced by elicited peritoneal macrophages of WT, COX-1-/- and COX-2-/- mice indicated increased production of HETEs in COX-2-/- cells as compared to WT cells. In addition production of Th1 pro-inflammatory cytokines IFN and TNFa was significantly suppressed in COX-2-/- CD4 T cells. Previous studies have demonstrated a requirement of 5-lipooxygenase derived products especially leukotrienes for T cell activation including cytokine production, and have also indicated that certain isomers of HETEs like 15-HETE can inhibit 5-lipooxygenase activity. These results coupled with our observations suggest that COX-2 potential of imparting negative regulatory signals on effector functions of lymphocytes We next addressed the question, whether the phenotypix characteristics of COX-2-/- mice can be attributed to an immediate deficiency of COX-2 derived products, or whether they are a result of physiological changes induced by COX-2 gene ablation. We compared the incidence of CIA in WT mice treated with a COX-2 selective inhibitor (Rofecoxib) as well as in COX-2-/- mice with respect to CIA susceptibility were only partially mimicked by prolonged administration of the COX-2 selective inhibitor to WT mice. These included suppression of the anti-CII humoral response, and reduced incidence and severity of disease. In addition an infusion of WT spleen cells could only partially restore susceptibility to CIA in COX-2-/- mice while the anti-CII humeral response remained suppressed Taken together these findings suggest that the prevention of CIA in COX-2-/- mice appears to results from the cumulative effects produced by COX-2 deficiency and the alteration in the arachidonic acid (AA) metabolism induced by COX-2 gene ablation. While COX-2 deficiency appears to enhance the susceptibility of B cells and macrophages to activation induced apoptosis, the altered repertoire of eicosanoids produced in COX-2-/- mice may be selectively activating the negative regulatory circuits of the immune and inflammatory systems

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: cyclooxygenase-1, cyclooxygenase-2, arthritis, immune system, b cells, macrophages, eicosanoids, lymphocytes, arachidonic acid (aa), apoptosis
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Depositing User: Unnamed user with email
Date Deposited: 19 Jul 2017 09:36
Last Modified: 19 Jul 2017 09:36

Actions (login required)

View Item View Item