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 17β-estradiol 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 17β-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 state/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. Finally docking studies were conducted with key ligands 17β-estradiol and norepinephrine to understand the mechanistic principles underlying their interactions. Adrenergic activation triggered pro-apoptotic signals while 17β-estradiol enhanced survival signals showing contradictory effects as observed in vitro. Treatment of lymphocytes with 17β-estradiol shows ten-fold increase in survival signals concentration-dependently manner. cAMP activation is crucial for the activation of survival signals through p-ERK (Extracellular Signal-Regulated Kinase) and p-CREB (cAMP Responsive Element Binding (protein). Inhibition of p-ERK by norepinephrine and β2-AR by 17β-estradiol indicate direct influence on the down-stream signals altering apoptotic v/s survival signals. Thus, the cross-talk between 17β-estradiol and adrenergic signaling pathways determines lymphocyte functions in a receptor subtype- and co-activation-dependent manner in health and disease.