The effects of protein kinase inhibitors on lymphocyte blastogenesis and GVHD-induced splenomegaly.
The activation of the protein kinase C (PKC) pathway plays an integral part in the proliferation of many cell types including lymphocytes. We report that the PKC inhibitor H-7 caused inhibition of three commonly studied blastogenic responses (Con A, LPS, and MLR) with the strongest suppression being detected in the MLR. In contrast, HA1004, a potent inhibitor of cyclic nucleotide-dependent protein kinases, did not alter the blastogenic response but occasionally caused augmentation. The phenothiazine compounds studied inhibited the Con A and, to a lesser extent, the LPS responses. One of the compounds, promethazine-HCl, was effective in vivo in inhibiting splenomegaly resulting from the induction of graft vs. host disease. Our studies support the involvement of PKC in lymphoid blastogenesis. They also suggest that agents that can inhibit PKC activity may be useful in inducing immunosuppression in vivo.
Wepsic
H T
HT
Department of Laboratory Service, Edward J. Hines, Jr., Veterans Administration Hospital, Hines, Illinois 60141.
Duffie
G P
GP
Ellis
N K
NK
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D006086:Graft vs Host Disease / Q000276:immunology; D007166:Immunosuppressive Agents; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010640:Phenothiazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D013163:Splenomegaly / Q000276:immunology; D013449:Sulfonamides
D007166:Immunosuppressive Agents; D007546:Isoquinolines; D010640:Phenothiazines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide