Enzyme defects in immunodeficiency diseases

Hirschhorn, Rochelle; Martin, David W.

doi:10.1007/bf01891819

Cited by 18 publications

(1 citation statement)

References 111 publications

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“…Guanosine, GMP, and cGMP have been shown to stimulate DNA synthesis in human bone marrow cells under serum-free conditions; in human serum, however, guanosine compounds were inhibitory (27). Deoxyguanosine appears to be responsible for lymphocytotoxicity to T cells in patients deficient in purine nucleoside phosphorylase (28). Phytohemagglutinin-induced transformation of human lymphocytes has been shown to be inhibited by GMP, GDP, GTP, and cyclic GMP (29).…”

Section: Resultsmentioning

confidence: 99%

Activation of lymphocytes by brominated nucleoside and cyclic nucleotide analogues: implications for the "second messenger" function of cyclic GMP.

Goodman¹,

Weigle²

1981

Proc. Natl. Acad. Sci. U.S.A.

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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 ofserum. 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 > 8-bromo GMP (8-BrGMP) > 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 Iymphocyte 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 (#i) cast significant doubt on the role of cGMP as an intracellular second messenger in lymphocyte proliferation.The role of cyclic nucleotides as mediators regulating lymphocyte activation and differentiation has been hotly contested for a number of years. Evidence suggesting that cyclic GMP (cGMP) and cyclic AMP (cAMP) regulate the inductive pathway in B cells whereas cAMP alone mediates the paralytic pathway (1) was followed by reports implicating cGMP as the "second messenger" for B-cell activation. Thus, mitogenic agents were found to increase intracellular cGMP but not cAMP (2, 3), and cGMP itself (2, 4, 5) and cGMP analogues (6-8) added exogenously to culture were shown to have mitogenic properties. However, other investigators were unable to corroborate enhancement of cGMP content by mitogens but noted instead small increases ofcAMP (9, 10). Still others found that changes in cyclic nucleotide concentrations failed to correlate with the mitogenic or nonmitogenic nature of the probe (11-13). In addition, many agents that increase cGMP are entirely nonmitogenic (14) or even inhibit mitogenesis (15). Reports that cGMP and cholinergic agonists stimulate the phosphorylation of lymphocyte proteins by protein kinase (16) have been countered with data to the contrary (17).Our data indicate that whereas exogenous cGMP has insignificant mitogenic potential itself, 8-bromo cyclic GMP (8-BrcGMP) has significant activity. This activity, however, is orders of magni...

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Section: Resultsmentioning

confidence: 99%