Role of protein kinase C in cyclic AMP-mediated suppression of T-lymphocyte activation following burn injury.
Major burn injury induces T-lymphocyte dysfunction. Previous studies suggest that prostaglandin (PG) E2, which is elevated post-burn, is the causative factor via a cyclic AMP-dependent process. The present study was conducted to elucidate the mechanism by which cAMP induces T-lymphocyte dysfunction following burn injury. Splenocytes were isolated from mice 7 days after receiving a scald burn covering 25% of their total body surface or sham procedure. ConA-induced proliferation by splenocytes from burned mice was significantly suppressed. Macrophage depletion of the splenocyte cultures abrogated the suppression. Concanavalin A-stimulated proliferation by macrophage-depleted splenocytes was suppressed by PGE2 and dibutyryl cAMP in both groups. The IC50 of these cAMP-elevating agents, however, was approximately 100-fold lower for cells from burned mice, indicating an increased sensitivity to cAMP. PGE2 did not suppress PMA/Ca2+ ionophore-induced T-lymphocyte activation. Addition of PMA to ConA-stimulated cultures prevented the suppression of proliferative responses by PGE2, whereas Ca2+ ionophore had no effect. Thus, the suppression of T-lymphocyte activation following burn injury is macrophage-dependent, related to an increased sensitivity to cAMP and due to an uncoupling of cell surface receptors from protein kinase C activation.
Schwacha
M G
MG
Department of Surgery, Brown University School of Medicine, Providence, RI 02903, USA. mschwacha@lifespan.org
Ayala
A
A
Cioffi
W G
WG
Bland
K I
KI
Chaudry
I H
IH
D000818:Animals; D002056:Burns / Q000209:etiology / Q000276:immunology*; D003208:Concanavalin A / Q000037:antagonists & inhibitors; D000242:Cyclic AMP / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D007165:Immunosuppression Therapy; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011493:Protein Kinase C / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D007376:Interleukin-2; D003208:Concanavalin A; D000242:Cyclic AMP; D011493:Protein Kinase C; D015232:Dinoprostone