Inhibition of protein-kinase C in peripheral blood mononuclear cells of patients with systemic lupus erythematosus: effect on spontaneous immunoglobulin production.
Systemic Lupus Erythematosus (SLE) is a multisystem disease characterized by an increase in the spontaneous secretion of immunoglobulin (Ig) molecules, many of which are autoreactive. We have previously shown (Biochem & Biophys. Res. Comm. (1989) 161: 1319-1326) that normal human peripheral blood mononuclear cells (PBMCs) can be stimulated to secrete large quantities of Ig upon incubation with the protein kinase-C activator 1 oleoyl-2-acetyglycerol (OAG). Specific blockage of protein kinase C with the isoquinoline sulfonyl piperazine compound (H-7) inhibited the OAG-induced Ig production. In experiments reported here, PBMC of 5 patients with active SLE produced high levels of IgG spontaneously in culture. PBMC of 6 inactive SLE patients and 7 normal control subjects produced comparable low levels of IgG spontaneously. Pokeweed mitogen (PWM) stimulation of PBMC in inactive SLE and control groups, but not active SLE patients produced markedly enhanced IgG production. The lack of response to PWM stimulation in active SLE patients is likely due to inherent maximal stimulation of active SLE B-cells. In addition, we examined the ability of H-7 to inhibit both mitogen-stimulated (normal and inactive SLE) and spontaneous (active SLE) Ig production. In other experiments, we also examined the ability of the isoquinoline sulfonamide (HA-1004), a potent inhibitor of cAMP-dependent protein kinase to regulate mitogen stimulated and spontaneous Ig production in the patient groups indicated above. H-7 significantly inhibited PWM stimulated Ig production in normal (P less than 0.0001) and inactive SLE patients, (P less than 0.040) suppressing PWM stimulated levels to spontaneous levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Chong
P
P
Pediatric Renal Immunology Laboratory, Steven Speilberg Pediatric Research Center, Ahmanson Pediatric Center, Los Angeles, CA.
Matzner
W L
WL
Yamiguchi
D
D
Wallace
D
D
Klinenberg
J R
JR
Jordan
S C
SC
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000328:Adult; D001323:Autoantibodies / Q000032:analysis*; D002478:Cells, Cultured / Q000187:drug effects; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis* / Q000097:blood; D007546:Isoquinolines / Q000494:pharmacology*; D008180:Lupus Erythematosus, Systemic / Q000097:blood*; D008297:Male; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D010879:Piperazines / Q000494:pharmacology*; D011043:Pokeweed Mitogens; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000097:blood; D013449:Sulfonamides
D001323:Autoantibodies; D007074:Immunoglobulin G; D007546:Isoquinolines; D010879:Piperazines; D011043:Pokeweed Mitogens; D013449:Sulfonamides; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D011493:Protein Kinase C