Protein restriction decreases plasma concentrations of albumin and insulin-like growth factor-I (IGF-I) by reducing their hepatic mRNA levels, whereas protein restriction increases IGF-I binding protein-2 (IGFBP-2) gene expression in the liver. Tumor necrosis factor (TNF), as an inducer of the injury response, decreases plasma albumin concentration and albumin mRNA in the liver. The present study was designed to evaluate the effects of protein repletion and TNF on plasma albumin and IGF-I and their mRNAs and IGFBP-2 mRNA in the liver of protein-restricted rats. After 2 weeks of feeding a 2% casein diet, rats were assigned to four groups according to either being refed with a 2% or 20% casein diet or receiving saline or TNF by intraperitoneal injection (50 microg/kg x d) for 4 days. Plasma IGF-I and albumin were assayed. Hepatic mRNAs of IGF-I, albumin, and IGFBP-2 were determined. Protein repletion increased plasma concentrations of IGF-I and albumin and their mRNA content in the liver, but decreased IGFBP-2 mRNA. TNF did not alter plasma IGF-I concentration but did increase hepatic IGF-I mRNA in protein-repleted animals, and plasma albumin concentration was significantly decreased with unaltered hepatic albumin mRNA. Thus, protein repletion of malnourished rats increased plasma IGF-I and albumin concentrations in association with increased expression of their mRNAs in the liver. However, plasma albumin but not IGF-I decreased following TNF in protein-restricted rats, whereas TNF increased hepatic IGF-I mRNA in protein-repleted rats. Thus, only plasma albumin concentration responds to both principal determinants, diet and injury, in the development of malnutrition.