The evidence for the integration of the submandibular gland (SMG) into the neuroimmunoregulatory network has been reviewed. In laboratory rodents, factors extracted from the SMG were shown to stimulate lymphocyte proliferation, to affect the weight of the thymus, spleen and lymph nodes and to induce immunosuppression in several in vivo animal models. The SMG produces significant quantities of nerve growth factor (NGF), epidermal growth factor (EGF), transforming growth factor-β and kallikreins, which are secreted into the saliva and affect immune and mucosal tissues and nerve endings in the gastrointestinal tract. These factors play a role in regulating mucosal immuno/inflammatory response and in regeneration and healing. The major salivary glands also produce antimicrobial proteins and secretory IgA antibodies which are essential factors in mucosal host defense. SMG-derived NGF, EGF and glandular kallikrein are delivered into the bloodstream where they may act as important systemic immunoregulators and also have major regulatory influences on the central neuroendocrine system. There is evidence to indicate that EGF is involved in the regulation of gonadal function. Growth hormone, prolactin, androgens, thyroid hormone and corticosteroids regulate protein synthesis in the SMG, whereas secretory activity is regulated by sympathetic (α- and β-adrenergic) parasympathetic (muscarinic) and peptidergic (substance P and vasoactive intestinal peptide) nerve fibers. Fluid and electrolyte secretion is promoted by parasympathetic, whereas protein secretion is stimulated by sympathetic nerve impulses. Steroid hormones and cytokines (interleukin-1α, -β, tumor necrosis factor, interferon-γ) have a major regulatory influence on protein secretion, including the secretion of immunoglobulin into the saliva. The SMG interacts with the mucosal and systemic compartments of the immune system, with the central and peripheral nervous systems, with the pituitary gland, and with peripheral endocrine organs. These interactions enable the SMG to exert regulatory influences on immune/inflammatory reactions in the gastrointestinal tract, in the lungs, and possibly elsewhere. It is suggested that these functions make this gland a key regulatory organ in the neuroimmunoregulatory network. Evidence is increasing that the major salivary glands fulfill similar functions in other species, including humans.

No abstract

No abstract

No abstract

No abstract

No abstract

No abstract

A protein of 40 kD molecular weight was isolated from the salivary submandibular glands of male rats. The protein catalyzed the hydrolysis of α-N-benzoyl-L-arginine ethyl ester. This esterase activity was inhibitable with the protease inhibitor aprotinin. The sequence of the first 25 amino acids of this protein was identical to that of rat glandular kallikrein (rGK). When added to cultures of murine lymph node cells suboptimally stimulated with the T cell mitogen concanavalin A, rGK markedly stimulated the proliferative activity of these cells. When injected into mice, rGK suppressed the contact sensitivity response to picryl chloride, a form of delayed-type hypersensitivity. Similar in vitro and in vivo effects were induced with GK from porcine pancreas (pGK). Moreover, the aforementioned in vitro and in vivo effects were abolished by aprotinin either added to the tissue culture medium or injected into the animals immediately before rGK or pGK. This demonstrates that the enzymatic activity of rGK and pGK is important for the induction of immunoregulatory effects. These results suggest that rGK is a systemic immunoregulatory enzyme with immunosuppressive potential. GK is the first example for systemic immunoregulation by an enzyme, the secretion of which is under neuroendocrine control.