%0 Journal Article
%T Small molecule inhibition of 6-phosphofructo-2-kinase suppresses t cell activation
%A Sucheta Telang
%A Brian F Clem
%A Alden C Klarer
%A Amy L Clem
%A John O Trent
%A Richard Bucala
%A Jason Chesney
%J Journal of Translational Medicine
%D 2012
%I BioMed Central
%R 10.1186/1479-5876-10-95
%X We examined PFKFB1-4 and TIGAR expression and F2,6BP concentration in purified CD3+ T cells stimulated with microbead-conjugated agonist antibodies specific for CD3 and the co-stimulatory receptor, CD28. We then determined the effect of 3PO on anti-CD3/anti-CD28-induced T cell activation, F2,6BP synthesis, 2-[1-14C]-deoxy-D-glucose uptake, lactate secretion, TNF-¦Á secretion and proliferation. Finally, we examined the effect of 3PO administration on the development of delayed type hypersensitivity to methylated BSA and on imiquimod-induced psoriasis in mice.We found that purified human CD3+ T cells express PFKFB2, PFKFB3, PFKFB4 and TIGAR, and that anti-CD3/anti-CD28 conjugated microbeads stimulated a >20-fold increase in F2,6BP with a coincident increase in protein expression of the PFKFB3 family member and a decrease in TIGAR protein expression. We then found that exposure to the PFKFB3 small molecule antagonist, 3PO (1¨C10£¿¦ÌM), markedly attenuated the stimulation of F2,6BP synthesis, 2-[1-14C]-deoxy-D-glucose uptake, lactate secretion, TNF-¦Á secretion and T cell aggregation and proliferation. We examined the in vivo effect of 3PO on the development of delayed type hypersensitivity to methylated BSA and on imiquimod-induced psoriasis in mice and found that 3PO suppressed the development of both T cell-dependent models of immunity in vivo.Our data demonstrate that inhibition of the PFKFB3 kinase activity attenuates the activation of T cells in vitro and suppresses T cell dependent immunity in vivo and indicate that small molecule antagonists of PFKFB3 may prove effective as T cell immunosuppressive agents.
%K Glycolysis
%K 6-Phosphofructo-2-kinase/fructose-2
%K 6-bisphosphatase
%K Fructose-2
%K 6-bisphosphate
%K T cell
%U http://www.translational-medicine.com/content/10/1/95/abstract