Immune-endocrine interactions have recently been identified as an important, and perhaps central, mechanism for regulation of the immune and endocrine systems. Numerous endocrine hormones have been shown to regulate immune responses. Conversely, a number of protein products produced by cells of the immune system (cytokines and lymphokines) have been shown to regulate endocrine hormone activity. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure alters the activity of several immunoregulatory hormones, including glucocorticoids, estrogen, thyroxine, and prolactin. Preliminary data from our laboratory have shown that TCDD exposure results in an enhanced inflammatory response following antigen challenge. We postulate that enhanced inflammatory cytokine production accompanies the enhanced inflammatory response. Two of the major inflammatory cytokines [IL-1 and tumor necrosis factor (TNF)], have been shown to alter endocrine activity. When produced in pathological amounts, they also produce a cachectic response that resembles TCDD toxicity. Other cytokines produced during inflammation [e.g., PGE2, histamine] are immunosuppressive.
The specific aims of this grant are to define the roles of specific inflammatory cytokines and hormones in the suppression of the cytotoxic T lymphocyte (CTL) response by TCDD and to assess the interaction of hormones and cytokines with TCDD at the level of the macrophage (Mphi) and T cell.
Specific aim 1 will determine if prevention of corticosterone (CS) elevation or blockade of CS receptors in TCDD-treated animals alters the suppressive effects of TCDD on the CTL response.
Specific aim 2 will determine if the production of inflammatory cytokines (TNF, IL-1, PGE2) is altered in TCDD-exposed animals. Cytokine alterations will be measured at the level of transcription in macrophages (TNF and IL-1 mRNA) as well as systemically in TCDD-treated animals.
Specific aim 3 will determine if neutralization of TNF or PGE2 activity alters the elevation of circulating CS or the suppression of CTL activity in TCDD-exposed animals.
Specific aim 4 will determine the direct effect of TCDD on Mphi cytokine production and the effects of coexposure to TCDD and CS on Mphi cytokine production and CTL maturation in vitro. Based on the results of these studies, the extension of the model to assess other inflammatory cytokines (e.g., IL-6, histamine) and other immunoregulatory hormones (e.g., thyroxine, androgens) in TCDD-induced suppression of CTL activity will be initiated.
Showing the most recent 10 out of 19 publications
