PARTV. ROLEOF INTRACELLULAR FACTORSIN IMMUNITY
CYCLIC NUCLEOTIDES AND CALCIUM IN LYMPHOCYTE REGULATION AND ACTIVATION
*
John W. Hadden, Ronald G. Coffey, Radha Ananthakrishnan, and Elba M. Hadden Laboratory of lmmiinopharmacology Memorial Sloan-Kettering Cancer Center New York, New York 10021
Considerable evidence implicates the cyclic nucleotides, cyclic IP (CAMP) and cyclic GMP (cGMP), as key mediators of the actions of hormones. Jn general, the physiological events related to increases of cellular levels of one nucleotide are opposing to those related to increases in the other.' The lymphocyte, like other cells of the hematopoietic system, has a type of regulation in which cGMP is associated with the promotion of functions such as proliferation, cytotoxicity, lymphokine secretion, and rosette formation and cAMP is associated with inhibition of these functions.* Substances which have been linked to cGMP in the lymphocyte and the promotion of these functions include acetylcholine, carbachol, thymopoietin, thymosin, levamisole, imidazole, transfer factor, and lymphocyte-activating factor (LAF) . Substances which have been linked to cAMP and the inhibition of these functions include prostaglandin E, j3-adrenergic catecholamines, choleratoxin, theophylline, and histamine. These collected observations have been extensively reviewed.?, Because of restriction of manuscript length, this paper will confine itself to recent studies published since these reviews and will focus on the controversial areas.
CYCLIC NUCLEOTIDES IN LYMPHOCYTE REGULATIONBY HORMONES Within the context of hormone action on lymphocytes, three areas are particularly unclear, thus controversial. They concern the roles of cyclic nucleotides in ( 1) lymphocyte differentiation; (2) intracycle regulation of thymocyte proliferation; and (3) antibody production. Recent advances in the detection of cell surface markers on lymphocytes have made possible the determination of lymphocyte differentiation in shortterm culture. In essence, partially purified lymphocyte precursors from bone marrow or spleen can be induced by a variety of agents to display on their surface markers characteristic of thymus-derived lymphocytes ( B , TL, LY, HTLA, E rosette, etc.) . Pharmacological experiments indicate that cAMP and agents which increase cAMP (endotoxin, poly A:poly U, isoproterenol, prostaglandin, and theophylline) will promote the differentiation of both prothymocytes and pro-B The induction of differentiation can be antagonized by cGMP and agents which increase cGMP (acetylcholine, insulin, and imidazole) . This indirect evidence indicates that cAMP is involved in the induction of lymphocyte differentiation.
* This work was supported by grants from the National Institutes of Health (CA08748, CA-09149), The American Cancer Society, and the W.Alton Jones Foundation. 24 1 0077-8923/79/0332-0241 $01.75/0 @ 1979, NYAS
242
Annals New York Academy of Sciences
The natural inducers of thymocyte differentiation are thought to be the thymic hormones, of which thymopoietin, thymosin (a,),and facteur thymique serique have been purified and sequenced. Despite extensive efforts, none of these hormones have been shown to increase cAMP in prothymocytes.6-8 While the lack of effect of these hormones on cAMP levels might be explained by concomitant cAMP decreases in pro-B cells contaminating the preparations or insufficient purification of the prothymocyte, it seems likely that if an increase occurs it is of less magnitude (
CYCLIC NUCLEOTIDES AND CALCIUM IN LYMPHOCYTE REGULATION AND ACTIVATION
*
John W. Hadden, Ronald G. Coffey, Radha Ananthakrishnan, and Elba M. Hadden Laboratory of lmmiinopharmacology Memorial Sloan-Kettering Cancer Center New York, New York 10021
Considerable evidence implicates the cyclic nucleotides, cyclic IP (CAMP) and cyclic GMP (cGMP), as key mediators of the actions of hormones. Jn general, the physiological events related to increases of cellular levels of one nucleotide are opposing to those related to increases in the other.' The lymphocyte, like other cells of the hematopoietic system, has a type of regulation in which cGMP is associated with the promotion of functions such as proliferation, cytotoxicity, lymphokine secretion, and rosette formation and cAMP is associated with inhibition of these functions.* Substances which have been linked to cGMP in the lymphocyte and the promotion of these functions include acetylcholine, carbachol, thymopoietin, thymosin, levamisole, imidazole, transfer factor, and lymphocyte-activating factor (LAF) . Substances which have been linked to cAMP and the inhibition of these functions include prostaglandin E, j3-adrenergic catecholamines, choleratoxin, theophylline, and histamine. These collected observations have been extensively reviewed.?, Because of restriction of manuscript length, this paper will confine itself to recent studies published since these reviews and will focus on the controversial areas.
CYCLIC NUCLEOTIDES IN LYMPHOCYTE REGULATIONBY HORMONES Within the context of hormone action on lymphocytes, three areas are particularly unclear, thus controversial. They concern the roles of cyclic nucleotides in ( 1) lymphocyte differentiation; (2) intracycle regulation of thymocyte proliferation; and (3) antibody production. Recent advances in the detection of cell surface markers on lymphocytes have made possible the determination of lymphocyte differentiation in shortterm culture. In essence, partially purified lymphocyte precursors from bone marrow or spleen can be induced by a variety of agents to display on their surface markers characteristic of thymus-derived lymphocytes ( B , TL, LY, HTLA, E rosette, etc.) . Pharmacological experiments indicate that cAMP and agents which increase cAMP (endotoxin, poly A:poly U, isoproterenol, prostaglandin, and theophylline) will promote the differentiation of both prothymocytes and pro-B The induction of differentiation can be antagonized by cGMP and agents which increase cGMP (acetylcholine, insulin, and imidazole) . This indirect evidence indicates that cAMP is involved in the induction of lymphocyte differentiation.
* This work was supported by grants from the National Institutes of Health (CA08748, CA-09149), The American Cancer Society, and the W.Alton Jones Foundation. 24 1 0077-8923/79/0332-0241 $01.75/0 @ 1979, NYAS
242
Annals New York Academy of Sciences
The natural inducers of thymocyte differentiation are thought to be the thymic hormones, of which thymopoietin, thymosin (a,),and facteur thymique serique have been purified and sequenced. Despite extensive efforts, none of these hormones have been shown to increase cAMP in prothymocytes.6-8 While the lack of effect of these hormones on cAMP levels might be explained by concomitant cAMP decreases in pro-B cells contaminating the preparations or insufficient purification of the prothymocyte, it seems likely that if an increase occurs it is of less magnitude (
