Salivary gland peptides: their role in anaphylaxis and lipopolysaccharide (LPS)-induced inflammation

Abstract

Abstract About a decade ago, we published the first of a series of studies, which eventually led us to develop the concept of a sympathetic-superior cervical ganglion-submandibular gland axis, which appeared to regulate the release of immunosuppressive substances from the submandibular glands of rats. These putative mediators could suppress anaphylaxis and LPS-induced shock. We eventually discovered that the agents released from the salivary glands capable of producing, the suppression of these inflammatory responses were novel, small molecular weight peptides and our current work has focused on the actions of one of these (submandibular gland peptide-T: SGP-T) and its analogs on animal models of anaphylaxis and LPS-induced inflammation. SGP-T, as well as the C terminal tri-peptide FEG, are both potent inhibitors of intestinal and cardiovascular anaphylaxis in egg albumen-sensitized Hooded-Lister or Sprague Dawley rats. They also inhibit endotoxin-induced hypotension in Sprague Dawley rats. These results are a striking demonstration of the ability of these salivary gland peptides to inhibit early phase immune responses. We have shown that the D-isomer of FEG (feG) prevents the infiltration of leukocytes following injection of LPS into the peritoneum. Similarly, in another presentation, at this meeting, we show that feG can also block late phase responses in anaphylaxis by preventing infiltration of pulmonary tissue by leukocytes. In other models, we have been able to show that these peptides inhibit carrageenan-induced neutrophilia within the skin and inhibit leukocyte rolling and adhesion in mesenteric venules. Current work is focusing on the molecular mechanisms which lead to recruitment and activation of leukocytes into intestinal tissue following anaphylaxis and LPS activation. We will present data showing inhibition of expression of identified cell markers involved in chemotaxis and activation in both these models, which reveals some interesting differences between the two, suggesting that these peptides may act on different receptor subtypes. In summary, our collective work to date implies that there is an important sympathetic pathway, involving the superior cervical ganglion, that regulates the release of novel peptides from the submandibular glands which play an important part in early and late phase immune responses in anaphylaxis and LPS-induced inflammation. In future work we hope, not only to reveal the molecular mode of action of these peptides, but also to return to the point where we began and use our increasing molecular knowledge to study the neuroregulation of their production and release.