Following activation peritoneal macrophages from diabetes prone BB rats secreted strikingly higher amounts of tumour necrosis factor alpha than found for macrophages from diabetes resistant or normal Wistar rats. Enhanced tumour necrosis factor alpha production was detected prior to the occurrence of insulitis. Cultures of macrophages derived from precursor cells in diabetes prone BB rat bone marrow also showed upregulated tumour necrosis factor alpha secretion upon challenge with endotoxin and interferon gamma. Tumour necrosis factor alpha hypersecretion may contribute to autoimmune diabetes by affecting thymic and post-thymic T-cell maturation and by promoting pancreatic islet inflammation.