In silico modeling and simulation of neuroendocrine-immune modulation through adrenergic and 17β-estradiol receptors in lymphocytes show differential activation of cyclic adenosine monophosphate (cAMP)

Sympathetic innervation of lymphoid organs and presence of 17{beta}-estradiol (estrogen or E2) and adrenergic receptors (ARs) on lymphocytes suggests that sympathetic stimulation and hormonal activation may influence immune functions. Simulation of these pathways may help to understand the dynamics of neuroendocrine-immune modulation at the cellular and molecular level. Dose- and receptor-dependent effects of 17{beta}-estradiol and AR sub-type-specific agonists were established in vitro on lymphocytes from young male Sprague-Dawley rats and modeled in silico using MATLAB Simbiology toolbox. Kinetic principles were assigned to define receptor-ligand dynamics and concentration/time plots were obtained using Ode15s solvers at different time intervals for key regulatory molecules. Comparisons were drawn between in silico and in vitro data for validating the constructed model with sensitivity analysis of key regulatory molecules to assess their individual impacts on the dynamics of the system. Adrenergic activation triggered pro-apoptotic signals while 17{beta}-estradiol enhanced survival signals showing contradictory effects as observed in vitro. Treatment of lymphocytes with 17{beta}-estradiol shows ten-fold increase in survival signals in a dose-dependent manner. cAMP (cyclic adenosine monophosphate) activation is crucial for the activation of survival signals through p-ERK (Extracellular Signal-Regulated Kinase) and p-CREB (cAMP Responsive Element Binding) protein. Thus, the cross-talk between 17{beta}-estradiol and adrenergic signaling pathways determines lymphocyte functions in a receptor subtype- and co-activation-dependent manner in health and disease.