We have investigated the function of different mediators of the regulation of the human C-reactive protein (hCRP) gene in transgenic mice. hCRP was induced by lipopolysaccharide and wounding in interleukin-6 (IL-6) +/+ mice, but not in IL-6 -/- mice. This finding suggested that IL-6 is necessary for the induction of hCRP. However, injection of IL-6 did not induce the hCRP gene. Thus, the induction of hCRP by IL-6 seems to require an additional cofactor. Therefore, we screened different cytokines for their activity in IL-6 +/+ and IL-6 -/- mice. Surprisingly, interleukin-1beta, as well as oncostatin M or leukaemia inhibitory factor, led to an induction of hCRP in both genetic backgrounds. These results indicate an IL-6-dependent and -independent regulation of hCRP. These hCRP transgenic mice therefore represent a novel model system for defining the cytokine network involved in the regulation of acute-phase genes during the course of inflammation.