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We have recently demonstrated that 17 beta-estradiol (E2) inhibits peritoneal adhesion formation. Because macrophages play a central role in inflammation and wound healing, we chose to investigate whether the E2 could inhibit the expression of JE, the murine monocyte chemoattractant protein-1 (MCP-1). To accomplish this, murine fibroblasts were cultured with physiological concentrations of E2 (3-300 pg/ml) with or without inducers of JE/MCP-1 mRNA expression. Untreated cells failed to express the message, but, following stimulation, a marked increase in JE/MCP-1 mRNA expression was observed. At 10-30 pg/ml, E2 had no effect on JE/MCP-1 mRNA expression in stimulated fibroblasts. In contrast, lower and higher doses of E2 inhibited the expression of JE/MCP-1 mRNA in stimulated fibroblasts. Treatment with tamoxifen reversed the E2-inhibition of expression of the message. These data demonstrate that JE/MCP-1 mRNA expression is controlled, in part, by estrogen and suggest that macrophage recruitment may be affected by circulating levels of E2.

An important function of the sympathetic nervous system is to maintain homeostasis by modulating the level of cellular activity in many diverse organ systems. The sympathetic neurotransmitter norepinephrine modulates the level of T and B lymphocyte activity by binding to the beta2-adrenergic receptor (beta2AR). The present study was designed to elucidate the mechanism by which stimulation of the beta2AR affects both Th1/Th2 cell cytokine production and Th1/Th2 cell-dependent Ab production. Clones of murine Th1/Th2 cells were exposed to the beta2AR agonist terbutaline before activation by Ag-presenting B cells. Terbutaline exposure of Th1 cells before activation inhibited IFN-gamma production by Th1 cells and subsequent IgG2a production by B cells. IgG2a inhibition was prevented by addition of the betaAR antagonist nadolol or exogenous IFN-gamma. In contrast to Th1 cells, terbutaline did not affect either IL-4 production by Th2 cells or subsequent IgG1 production by B cells. Although baseline levels of intracellular cAMP were similar in both subsets, terbutaline induced an increase in cAMP levels in Th1 cells only. Radioligand binding studies showed that a detectable number of beta2AR binding sites were present on Th1 cells, but not on Th2 cells. Immunofluorescence analyses showed that Th1 cells expressed a higher level of the beta2AR cytoplasmic carboxyl terminus than did Th2 cells. These results show that expression of the beta2AR binding site by Th1 cells, but not by Th2 cells, establishes a physiologic mechanism for selective modulation of Th1 cell IFN-gamma production and IFN-gamma-dependent IgG2a production, provided that beta2AR stimulation occurs before cell activation by a B cell.

We recently reported that resting clones of murine Th1 cells, but not resting Th2 cells, expressed a detectable level of the beta-2-adrenergic receptor (beta 2AR). In the present study, we proposed that the level of beta 2AR expression on anti-CD3 mAb-activated CD4+ effector Th cells may differ from the level on resting cells, and that a change in receptor expression may alter the functional responsiveness of these cells to either the beta 2AR-selective ligand terbutaline or the sympathetic neurotransmitter norepinephrine. Following anti-CD3 activation, the beta 2AR was expressed on Th1 cells, but not Th2 cells. The number of binding sites on Th1 cells was maintained, with no change in affinity, over a 24-h activation period. When Th clones were exposed to terbutaline following anti-CD3 activation, Th1 cell, but not Th2 cell, cytokine production was modulated. IL-2 production by Th1 cells was decreased, while IFN-gamma production was not significantly altered. The decrease in IL-2 production was concentration dependent and was blocked by an antagonist. In comparison with control supernatants, the lower level of IL-2 present in terbutaline-exposed culture supernatants supported the proliferation of an IL-2-dependent Th1 clone to a lesser degree. Additionally, norepinephrine down-modulates IL-2, but not IFN-gamma, production by binding specifically to the beta-adrenergic receptor. Thus, a detectable level of the beta 2AR is expressed on activated Th1 cells, but not activated Th2 cells, thereby providing a mechanism by which IL-2 production is preferentially modulated by an endogenous and therapeutic ligand following Th1 cell activation.