We have investigated the effect of the in vivo administration of recombinant transforming growth factor  (rTGF-) on the pathogenic mechanisms involved in Salmonella typhimurium experimental infection in mice. The protective response elicited by macrophages was induced by rTGF-₁ by 2 days after experimental infection, as demonstrated by an increased NO production, while the humoral protective effect began with cytokine mRNA expression 2 days after the challenge and continued after 5 days with cytokine release and lymphocyte activation. We demonstrated that all mice who received rTGF-₁ survived 7 days after infection. The number of bacteria recovered in the spleens and in the livers of rTGF-₁-treated mice 2 and 5 days after infection was significantly smaller than that found in the same organs after phosphate-buffered saline (PBS) inoculation. Furthermore, 2 and 5 days after infection, splenic macrophages from rTGF-₁-treated mice showed a greater NO production than did those from PBS-treated mice. The effect of rTGF-₁ on S. typhimurium infection in mice was correlated with the expression of cell costimulatory CD28 molecules. Five days after S. typhimurium infection, the percentage of CD28⁺-expressing T cells in splenic lymphocytes from rTGF-₁-treated mice increased with respect to that from control mice. Gamma interferon (IFN-) mRNA was present in a greater amount in spleen cells from rTGF-₁-treated mice after 2 days, although the intensity of the band decreased 5 days after the challenge. A similar pattern was obtained with the mRNAs for interleukin-1 (IL-1), IL-6, TGF-, and inducible nitric oxide synthase, which showed greater expression in cells obtained from rTGF-₁-treated and S. typhimurium-infected mice 2 days after challenge. The treatment with rTGF-₁ induced an increase in IL-1 and IFN- release in the supernatant of splenocyte cultures 5 days after the experimental infection with S. typhimurium. Moreover, we demonstrated that 5 days after infection, the IFN- titer was significantly greater in the sera of rTGF--treated mice than in those of PBS-treated mice. Also, hsp60 showed greater expression 2 days after the challenge in splenocytes from rTGF-₁-treated mice. The role played by proinflammatory and immunoregulatory cytokines and by CD28 is discussed.