The regulation of interferon production by aspirin, other inhibitors of the cyclooxygenase pathway and agents influencing calcium channel flux

Abstract

Interferon is a family of potent antiviral agents which can activate macrophages, enhance cell surface markers, or influence antibody production. Three major types of human interferon are known to exist and have been designated interferons alpha, beta, and gamma. Because of its unique antiviral properties and its ability to influence the immune response, interferon has long been considered a potential therapeutic intervention in the treatment of infections and possibly neoplastic diseases. Two potential means to utilize interferon might be considered: One method would involve the administration of exogenous interferon, but an alternative might augment natural interferon production. We have been investigating a series of pharmacological agents that might influence its production and action. Since prostaglandins influence the immune response, we have investigated the effect of these cyclic fatty acids and those agents that influence their production on soluble protein mediators of the immune response on interferon. Our studies have focused on the effects of acetylsalicylic acid on the interferon system. We have demonstrated that prostaglandins of the E series can significantly reduce the yields of human interferon gamma, but not alpha (the two species of leukocyte derived interferon). In general, yields of gamma interferon produced by peripheral blood mononuclear cells in the presence of PGE2 (0.1 to 0.01 ugm/ml) were approximately 15% of those produced in the absence of these substances. In contrast, when acetylsalicylic acid (10 ugm/ml) was added to the cultures of peripheral blood mononuclear cells yields of gamma interferon increased more than threefold. When examining the effects of acetylsalicylic acid on human alpha interferon production, we were also to enhance interferon harvests although we could not demonstrate an adverse effect of prostaglandins on the production of these bioactive proteins. Addition of acetylsalicylic acid and prostaglandins simultaneously to our cultures had a negative effect on gamma interferon production, but still was associated with enhanced yields of interferon alpha. In examining how prostaglandins might influence interferon production, we began to study other cellular requirements for lymphokine production including those processes which were calcium dependent. Preliminary studies demonstrated that production of human interferon gamma by peripheral blood mononuclear cells was calcium dependent, but production of human interferon alpha was not. Thus, almost all agents studied that influenced calcium dependent intracellular processes influenced the titer of human interferon gamma produced, but not that of human interferon alpha. In examining this phenomenon more closely we noted the calcium channel flux was critical to the production of interferon gamma, hence agents enhancing channel flux(Bay K 8644) increased the production of human interferon gamma, but agents diminishing channel flux (specifically) channel blockers diminished production of this interferon species. These effects depended on the nature of the specific inducing agent. We are now examining the relationship of our observations with calcium to our earlier work with acetylsalicylic acid.