Neuroimmunomodulation: classical and non-classical cellular activation

As neuroimmunologists, we are often faced with the fact that some substances can either enhance or inhibit particular immune/inflammatory cell functions. This 'duality' could only partially be explained by dose-dependency and the fact that in a variety of systems, heterogenous cell populations are commonly used. For example it has been repetitively shown that cell proliferation, immunoglobulin synthesis and NK (natural killer) activity could be enhanced, inhibited or not affected at all by such neuropeptides as somatostatin (SOM) or vasoactive intestinal peptide (VIP), depending on the experimental conditions. Even substance P (SP), which, in general, stimulates lymphocyte activity, can, under certain conditions, possess an inhibitory activity. These apparent discrepancies between various groups and experimental conditions met with a strong reservation among 'classical' immunologists as they questioned the true physiological role that neuro-immune interactions play in normal and disease states. However, upon a detailed analysis of the data, it become obvious why such discrepancies abounded. Not only are we comparing totally different responses in different species, but almost always we compare different experimental conditions. In lieu of this, the reproducibility of the experiments within the same laboratory is in fact very high. One fundamental and striking observation is the fact that at the level of a homogeneous cell population, a differential response could be evoked by the same neuropeptide over a range of concentrations. For the purpose of this brief report we will focus on the cellular responses to the neuropeptide substance P and we will try to illustrate why such differential responses are possible. Some of the physiological data relating to the effects of SP on cell function will be discussed. This will be followed by a synopsis of SP receptor mechanisms on effector cells and finally the mechanism by which SP activates secondary messenger systems in these cells.