Activation of lymphocytes by brominated nucleoside and cyclic nucleotide analogues: implications for the "second messenger" function of cyclic GMP.
The purine nucleoside guanosine, when derivatized at the C-8 position to give 8-bromoguanosine (8-BrGuo), acquires the capacity to stimulate high-level lymphocyte proliferation in the presence or absence of serum. Direct comparisons were undertaken to determine whether this activity is exerted only by virtue of the structural resemblance of 8-BrGuo to 8-bromo cyclic GMP (8-BrcGMP) (a known intracellular lymphocyte mitogen). They showed that, of the brominated guanosine derivatives studied, 8-BrGuo is the primary activator because (i) it is a far more potent lymphocyte activator than 8-BrcGMP, the order of mitogenic potency being 8-BrGuo greater than 8-bromo GMP (8-BrGMP) greater than 8-BrcGMP; (ii) it acts much more rapidly than 8-BrcGMP; (iii) it is not metabolized to 8-BrcGMP or cGMP; and (iv) it does not elevate intracellular cGMP content. cGMP is not likely to be the second messenger serving to activate B cells because (i) it does not induce significant proliferation unless brominated at the C-8 position; (ii) the brominated form is much less efficient than 8-BrGuo or 8-BrGMP; (iii) 8-BrGuo and many other mitogens do not increase intracellular cGMP; (iv) many agents that increase cGMP fail to initiate lymphocyte activation; (v) certain agents that increase cGMP (i.e., 15-hydroperoxyarachidonic acid, azide) inhibit lymphocyte activation; and (vi) addition of unbrominated cGMP to cultures stimulated with 8-BrGuo actually diminished stimulation. These data (i) indicate that, by interaction with cellular components, 8-BrGuo triggers high level lymphocyte activation and (ii) cast significant doubt on the role of cGMP as an intracellular second messenger in lymphocyte proliferation.
D015124:8-Bromo Cyclic Adenosine Monophosphate; D000818:Animals; D001692:Biological Transport; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D006152:Cyclic GMP / Q000502:physiology*; D006150:Guanine Nucleotides / Q000378:metabolism; D006151:Guanosine / Q000031:analogs & derivatives; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000502:physiology*; D008297:Male; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D013329:Structure-Activity Relationship; D013997:Time Factors
D006150:Guanine Nucleotides; D006151:Guanosine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D006157:Guanosine Monophosphate; D000242:Cyclic AMP; D006152:Cyclic GMP