Adjuvant-induced arthritis (AIA) is an animal model of inflammatory joint disease that mimics rheumatoid arthritis (RA). In the rat, it is induced by the injection of Mycobacterium butyricum (MBB) into the base of the tail. Symptoms characterized by paw and joint swelling appear 11-14 days after MBB treatment. On the other hand, changes in neuroendocrine functions, in particular activation of the hypothalamic-pituitary-adrenal (HPA) axis, occur significantly earlier. We therefore propose the following: (a) Increases in the hormones of the HPA axis, namely corticotropin-releasing factor (CRF), ACTH and corticosterone result from the augmented production of immune proteins called cytokines [in particular tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6)]. (b) The cross-talk between the immune system and the HPA axis of AIA rats provides an amplifying mechanism for the inflammatory process.
Under Specific Aim 1, we will test the first hypothesis by measuring cytokine levels in the plasma and the brain of AIA and control rats. We will then administer a TNFalpha soluble receptor to determine if it prevents or reverses the activation of the HPA axis. Our second hypothesis is that CRF, originally known for its ability to release ACTH but later demonstrated to influence immune functions, participates in the increased cytokine formation.
Under Specific Aim 2, we will test this hypothesis by measuring cytokine concentration s in rats injected with CRF antagoinsts. Neuroendocrine changes in RA patients have traditionally been considered secondary to the pain and discomfort of the arthritic process. We proposed that while this may be partically true, specific changes in immune functions play an important role in the subsequent alteration sin the HPA axis activity and that conversely, activationof the HPA axis influences cytokine production . CRF, ACTH, and cortiscosteroids exert significant effects on energy metabolism, mood, and reproductive functions, which may synergize with arthritis sympotoms to aggravate this condition. Cytokines play a proinflammatory role and worsen rheumatoid synovitis. Together, these observations make a powerful case for the investigation of the mechanisms responsible for the appearance of these secretagogues, and the development of therapies designed to prevent or revers them.
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