Nitric Oxide Produced by Macrophages Mediates Suppression of ConA-Induced Proliferative Responses of Splenic Leukocytes in the Diabetes-Prone BB Rat

Splenic cells from the diabetes-prone BB rat show reduced proliferative responses to concanavalin A (ConA) and other mitogens. This study was undertaken to test whether this reduced lymphoproliferation in the BB rat is mediated by an increased production of nitric oxide (NO) by macrophages. Splenic leukocytes from diabetes-prone BB rats and five strains of control rats (BB-R, Wistar-Furth, Sprague-Dawley, Wistar, and Lewis) were cultured in RPMI-1640 media containing ConA. The leukocytes from BB rats showed reduced [³H]thymidine uptake and increased release of NO compared with the control rats. Partial depletion of macrophages from the culture or incubation with N^G-monomethylarginine (NGMMA), a specific NO synthase inhibitor, markedly augmented ConA-induced proliferation of the splenic leukocytes from BB but not the control rats. Enrichment of BB rat macrophages suppressed the proliferation of BB-R rat spleen cells. Excess L-arginine added to the culture reversed the NGMMA effect. These results suggest that increased production of NO by macrophages is partly responsible for the reduced proliferative responses of splenic leukocytes in the BB rat.