Tamoxifen (at 0.1-1 microM concentrations) inhibited significantly the response of rat spleen cells to phytohemagglutinin, concanavalin A, pokeweed mitogen and lipid A in a dose-dependent manner. To achieve this inhibition, it was sufficient to expose the lymphocytes for 4 h to tamoxifen prior to mitogenic stimulation. Estradiol did not have a consistent effect on lymphocyte mitogenesis under the same conditions and did not modify the suppressive effect of tamoxifen, even when the lymphocytes were treated first with estradiol followed by tamoxifen. It is suggested that the inhibitory effect of tamoxifen on these in vitro lymphocyte reactions is not mediated by the estrogen receptor.

Animals↗

PubMedDate not supplied

The influence of estradiol and tamoxifen on the mixed lymphocyte reaction in rats.

The effect of estradiol and of the anti-estrogenic agent, tamoxifen, on mixed lymphocyte reactions was examined in the rat. Tamoxifen exerted a consistent inhibiting effect at concentrations ranging from 0.4-400 ng/ml. Estradiol was ineffective at physiological concentrations (0.4 ng/ml), whereas at pharmacological levels (400 ng/ml) significant inhibition was observed in some experiments but not in others. The inhibitory effect of both agents was more consistent in fetal calf serum containing medium when compared to that with autologous serum. Phenol Red had no effect on the outcome of these experiments.

Animals↗

PubMedDate not supplied

The role of the growth and lactogenic hormone family in immune function.

The influence of various members of the growth and lactogenic hormone family on the immune system is reviewed. A general hypothesis is proposed for growth control in higher animals. It is suggested that immune reactions, which are based on lymphocyte proliferation, obey the general rules of growth control in vertebrate animals. Growth and lactogenic hormones (GLH) are required for the development and function of the immune system and are suggested to deliver the first signal that prepares the cell for proliferation, differentiation and function. This signal has already been designated by other as the competence signal which initiates the cell cycle. Second signals are delivered through the antigen receptor, and/or by some other cell surface receptors (adhesion molecules) and always involve cell-to-cell ('bridging') and/or cell-to-matrix interaction. This category of signals is designated as stromal or adherence signals. The lymphocyte adhesion molecules that mediate second signals have evolved form organ- and tissue-specific recognition/regulatory molecules. The antigen receptors have been perfected during evolution from self recognition to specific-antigen recognition. Apart from this exquisitely specific mechanism of immune recognition, there is evidence for other less specific means of recognition by adherence molecules that mediate the activation of the immune system during nonspecific injury and also play a role in the elimination of degenerated and neoplastic cells. Signals delivered through adhesion molecules have the power to commit the cell to a given activity which is executed by the delivery of third signals in the form of soluble cytokines, usually, but not always, by the same cell delivering the second signal(s). The combination of these three groups of signals will ultimately determine whether or not the cell will proliferate, differentiate, maintain function or, perhaps, be committed to apoptosis. Therefore, GLH maintain immunocompetence which enables the immune system to respond to specific antigenic and tissue-derived stimuli in a self-regulated fashion. The adrenocorticotropic hormone-adrenal axis antagonizes the immunostimulatory effect of GLH. This basic pattern of lymphocyte regulation is influenced further by additional hormones, neurotransmitters and neuropeptides, mostly by the modulation of signal delivery. The constant interaction of neuroendocrine and internal immunoregulatory mechanisms assures the fine tuning of the immune system, so that it is able to function in homeostasis and harmony with the organism.

Animals↗

PubMedDate not supplied

The submandibular gland: a key organ in the neuro-immuno-regulatory network?

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-beta 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 (alpha- and beta-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-1 alpha, -beta, tumor necrosis factor, interferon-gamma) 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.

Animals↗

PubMedDate not supplied

Immunoregulatory effects of glandular kallikrein from the salivary submandibular gland of rats.

A protein of 40 kD molecular weight was isolated from the salivary submandibular glands of male rats. The protein catalyzed the hydrolysis of alpha-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.

Amino Acid Sequence↗