Biomedical Research 2003; 14 (1): 30-37

The submandibular glands contain and secrete a large number of physiologically active proteins and peptides such as digestive enzymes, growth factors, homeostatic proteases and regulatory proteins and peptide hormones [1, 2]. These molecules subserve a range of biological functions essential for the maintenance of the health and the functioning of the oral cavity and the digestive tract [1, 36]. However, they also participate in physiological adjustments related to the maintenance of systemic immunological and physiological homeostasis [7,8]. For example an endocrine function for nerve growth factor (NGF) released from salivary glands was established in the 1970’s [9]. Subsequently, a significant relationship between the endocrine function of the salivary glands and social behaviour in mice was described [10,11] suggesting a potential role for the autonomic nervous system in regulating release of NGF. Immunomodulatory influences exerted by salivary glands, which include the healing of oral peripheral and internal wounds [5,12]) and the regulation of systemic inflammatory reactions [13-16] have been described. Where studied all the regulatory functions of the salivary glands have been shown to be under central nervous system control and mediated by both the sympathetic and parasympathetic divisions of the autonomic nervous system (ANS). It was, therefore, highly probable that the immunoregulatory function of the salivary glands would likewise be under ANS control. This appears to be the case. The parasympathetic nerves stimulate the secretion of saliva containing small quantities of biologically active peptides with putative immunoregulatory functions [1]. β-adrenergic stimulation also increases the synthesis and release of these same peptides. However, α-adrenergic stimulation stimulates the secretion of growth factors and homeostatic proteases from cells into the blood and causes secretion of large amounts of kallikrein, NGF, epidermal growth factor (EGF) and renin into the saliva to a greater extent than β stimulation [17-20]. Direct stimulation of sympathetic nerves releases kallikrein into the saliva and blood [1]). Sympathetic nerves also regulate gene expression for NGF and EGF [21]. In the past twelve years considerable data have accumulated supporting the concept of a cervical sympathetic trunk— submandibular gland (CST-SMG), neuroendocrine regulatory axis that modifies inflammatory responses [7,22,23]. Following the defining of this physiological regulatory system two novel peptides were isolated from the submandibular glands of rats which exert antiinflammatory actions and which appear to be the endocrine mediators of this novel immunoregulatory system [15]. In the following sections we will first summarize the key evidence leading to the discovery of the CST-SMG axis then describe the isolation and identification of the putative SMG regulatory peptides. Finally, we will briefly discuss the physiological and immunomodulatory properties and the putative mechanism(s) of action of one of these peptides, submandibular gland peptide T (SGP-T).