The effect of deoxyguanosine on human lymphocyte function. II. Analysis of the interference with B lymphocyte differentiation in vitro.
The differentiation of normal human peripheral blood B lymphocytes into plasma cells in vitro, studied in mononuclear cells stimulated with PWM or in purified B cells stimulated with a T cell-replacing factor (TRF), can be inhibited by both deoxyguanosine (dGuo) and guanosine. The mechanism underlying this effect, which differs from the in vivo findings in PNP deficiency, was analyzed. dGuo toxicity can be antagonized by hypoxanthine but not by deoxycytidine. PNP-deficient and HGPRT-deficient B lymphocytes are not sensitive to the intoxicating properties of (deoxy)guanosine. Inhibition of PNP activity in normal B lymphocytes by 8-aminoguanosine decreases the sensitivity for dGuo intoxication. Incubation of purified B cells (stimulated with TRF) with dGuo leads to increased intracellular levels of guanosine di- and triphosphate (GDP and GTP), whereas deoxyguanosine triphosphate (dGTP) levels remain low. These observations lead to the conclusion that inhibition of B lymphocyte differentiation by dGuo is brought about by one of the end products of the pathway starting with degradation of dGuo by PNP, followed by guanine salvage by HGPRT, and possibly further phosphorylation of GMP into GDP and GTP. According to this mechanism, B lymphocyte differentiation in PNP deficiency is not sensitive to (deoxy)guanosine; because of the absence of PNP activity, these cells cannot accumulate GMP, GDP, and GTP, and therefore escape dGuo intoxication.
D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D003841:Deoxycytidine / Q000494:pharmacology; D003849:Deoxyguanosine / Q000494:pharmacology*; D006151:Guanosine / Q000494:pharmacology; D006801:Humans; D019271:Hypoxanthine; D007041:Hypoxanthine Phosphoribosyltransferase / Q000097:blood; D007042:Hypoxanthines / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015848:Interleukin-5; D008213:Lymphocyte Activation / Q000187:drug effects*; D008222:Lymphokines / Q000502:physiology; D010950:Plasma Cells / Q000276:immunology; D011683:Purine-Nucleoside Phosphorylase / Q000097:blood; D012265:Ribonucleotides / Q000097:blood
D007042:Hypoxanthines; D007166:Immunosuppressive Agents; D015848:Interleukin-5; D008222:Lymphokines; D012265:Ribonucleotides; D003841:Deoxycytidine; D006151:Guanosine; D019271:Hypoxanthine; D011683:Purine-Nucleoside Phosphorylase; D007041:Hypoxanthine Phosphoribosyltransferase; D003849:Deoxyguanosine