The role of the two types of tumor necrosis factor (TNF) receptors, TNF-R1 and TNF-R2, in mediating the capacity of TNF to stimulate nerve growth factor (NGF) production in fibroblasts has been investigated. Although Swiss 3T3 cells express both the TNF-R1 and TNF-R2, an agonistic anti-TNF R1 antibody, but not an agonistic anti-TNF-R2 antibody, increases the NGF mRNA level and stimulates the production of NGF protein in the cells. Treatment of the cells with a combination of anti-TNF-R2 antibody and interleukin-1 beta (IL-1 beta) does not increase the NGF production induced by IL-1 beta alone, although TNF's activity to stimulate NGF production is markedly enhanced by IL-1 beta. Furthermore, simultaneous addition of the both antibodies does not increase the NGF production above that observed with the anti-TNF-R1 antibody, indicating that TNF-R1 alone mediates the TNF's activity to stimulate NGF production in fibroblasts.