CYTOKINE REGULATION OF THE MUCOSAL IMMUNE-SYSTEM - INVIVO STIMULATION BY INTERFERON-GAMMA OF SECRETORY COMPONENT AND IMMUNOGLOBULIN-A IN UTERINE SECRETIONS AND PROLIFERATION OF LYMPHOCYTES FROM SPLEEN

The secretory immune system in the female reproductive tract is known to be regulated by sex hormones and antigen. The purpose of the present study was to examine the control by interferon-gamma (IFN-gamma) of the secretory component (SC), the polymeric immunoglobulin A (IgA) receptor, and IgA in uterine secretions and to determine whether IFN-gamma influences the proliferation of spleen cells in response to mitogens. When measured by RIA, SC levels in uterine secretions were elevated when increasing doses of IFN-gamma (1000-5000 U/uterus) were placed in the uterine lumen of ovariectomized rats. In contrast, IFN-alpha-beta (5000 U/uterus) placed in the uterine lumen had no effect on uterine SC levels. To determine whether IgA movement increases in response to IFN-gamma, animals were treated with estradiol to increase uterine tissue IgA levels without stimulating the accumulation of IgA or SC in uterine secretions. Under these conditions, intrauterine IFN-gamma increased SC and IgA levels in uterine secretions, suggesting that in vivo IFN-gamma stimulation of uterine SC increases the transport of IgA from tissue to lumen. Analysis of uterine tissues indicated that intrauterine IFN-gamma had no apparent effect on epithelial cell morphology. In contrast, intraepithelial lymphocytes and polymorphonuclear leucocytes, which were sparse in control tissues, increased markedly with IFN-gamma treatment. This increase was antagonized when estradiol was administered along with IFN-gamma. In other studies, IFN-gamma placed in the uterine lumen significantly increased spleen cell proliferation in response to Concanavalin-A, phytohaemagglutinin, and lipopolysaccharide mitogens relative to those in spleen cells from control animals. These studies demonstrate that in vivo treatment with IFN-gamma stimulates the mucosal immune system in the female reproductive tract by increasing SC and IgA levels in the uterine lumen and promoting the infiltration of intraepithelial lymphocytes and polymorphonuclear leucocytes into uterine tissue. Further, it suggests that antigen, in stimulating a local uterine response, may act through cytokines, particularly IFN-gamma, to regulate the transport of IgA into uterine secretions as well as modulate lymphocyte proliferation at sites distal to the uterus.