Induction and properties of cytoplasmic factor(s) which enhance nuclear nonhistone protein phosphorylation in lymphocytes stimulated by anti-Ig.

Abstract

The receipt and translation of the signals responsible for the activation of B cells to immunoglobulin (Ig)-producing cells is largely a cell surface phenomenon and the specificity of B-cell response resides in cell surface-associated Ig molecules [see references (1) and (2)]. However, in many experiments the signals given through Ig receptors by anti-lg antibodies have not been stimulative but often served as negative signals for differentiation of B cells to plasma cells unless they were accompanied or followed by some T-cell activities (3-6). A series of our previous experiments (7-9), in which a sequential stimulation of rabbit lymphocytes with anti-lg antibody (anti-lg) and T-cell-derived soluble products (SF) I induced IgG production, have suggested that the signals given through Ig receptors were essential for the activation of B cells.Receptor-ligand interaction on the surface of lymphocytes induces several morphological and biochemical changes in lymphocytes, such as capping (10), movement (11), increased transport of amino acids (12), changes of Ca ++ influx (13), and increase or decrease of intracellular level of cyclic nucleotides (14, 15). However, the molecular mechanism with which the signals given through Ig receptors are transduced across membranes so as to induce proliferation and/or differentiation of B cells is entirely unknown. So far many experiments have been done to explore the mechanism of the transmission of membrane-mediated signals. For example, the experiments done by Edelman and his collaborators (16) showed that microtubules were intimately involved in the movement of cell surface-associated receptors. The important role of the esterase activation in the induction of movements of B cells with anti-lg was shown by Becker and Unanue (17). It should be noted, however, that the relation of the modulation of cell surface receptors or lymphocyte movements to B-cell activation is entirely unknown.Recently, it has been shown in several experiments that nonhistone nuclear proteins have an important role in regulating the gene expression of eukaryotic cells (18). In lymphocytes, Johnson et al. (19) showed an increase of the amounts and phosphorylations of nonhistone nuclear proteins by stimulation with mitogens. Johnson and Hadden (20) also showed that cyclic GMP induced an increased phosphorylation of nonhistone proteins as well as proliferation of lymphocytes, suggesting that the phosphorylation of nonhistone nuclear proteins may be involved in the activation process of lyrnphocytes.

Antibody-induced changes in levels of cyclic adenosine monophosphate in leukaemic lymphocytes

“…Much less attention has been paid to the effects of antibody alone, since this has long been known not to be frankly cytotoxic for nucleated target cells (Ross & Lepow, 1960). However, more subtle effects on normal and neoplastic lymphoid cells due to antibody alone have been recorded, such as altered motility and various metabolic changes (Unanue et al, 1974;Nishizawa et al, 1977;Shearer & Parker, 1978). Furthermore, antibody has been reported to augment the susceptibility of neoplastic cells in vitro to X-rays and some cytotoxic drugs (Rubens et al, 1975).…”