Cortisol is regulated by a chain of signals: higher CNS areas to the hypothalmus to the pituitary to the adrenal gland. Cortisol regulation is abnormal in multiple sclerosis (MS) and depression. This insensitivity to feedback control interferes with steroid therapy of MS. 

Activated lymphocytes produce ACTH, a pituitary hormone. Since MS cells are activated, they may produce ACTH and cortisol and affect feedback control. We are investigating lymphocyte ACTH production and processing by using immunofluorescent stains, Western blots, and mRNA dot and Northern blots to quantify gene expression and regulation. 

Experimental allergic encephalomyelitis (EAE) is in some ways a model of MS. We find that IL-10 and prostaglandins inhibit clinical and histological EAE. As a direct result of these animal experiments, we found that PGE dramatically reduced the severe pain of trigeminal neuralgia in MS. 

 Lymphocyte products affect brain cell growth (IL-1), destroy brain cells (TNF), excite neurons (IFNs), and induce histocompatibility antigens (IFN-gamma, TNF-alpha). We have used cytokines to orchestrate expression of adhesion and MHC antigens on astrocytes. CD4+ cytolitic clones destroy the astrocytes, a model for rejection of transplanted brain tissues in Parkinson's disease. 

In MS, immune cells are intermittently out of control, invading the brain, and causing plaques of demyelination. We find that the B7 protein, needed for costimulation and lymphocyte activation is increased 4-fold in active disease. It is also present on microglia in MS plaques. 

Interferon-beta prevents attacks of MS through an unknown mechanism. IFN-treated patients have a decrease in the number of B7-1 positive B cells. The drop in B7-1 positive cells is a potential mechanism of action for this drug. IFN-beta inhibits monokine secretion but stimulates T cell production of mRNA for anti-inflammatory cytokines. We are using RT-PCR, gel shift assays, and phosphotyrosine blots to extend these investigations of cell-specific regulation of cytokine mRNA by IFNs, which should lead to more effective treatments of inflammatory diseases.