The acute-phase response is characterized by increased circulating levels of acute-phase proteins (APPs) generated by the liver. During bacterial pneumonia, APPs correlate with the severity of disease, serve as biomarkers, and are functionally significant. The kinetics and regulatory mechanisms of APP induction in the liver during lung infection have yet to be defined. Here we show that APP mRNA transcription is induced in the livers of mice whose lungs are infected with either Escherichia coli or Streptococcus pneumoniae, and that in both cases this induction occurs in tandem with activation in the liver of the transcription factors signal transducer and activator of transcription 3 (STAT3) and NF-kappaB RelA. Interleukin-6 (IL-6) deficiency inhibited the activation of STAT3 and the induction of select APPs in the livers of pneumonic mice. Furthermore, liver RelA activation and APP induction were reduced for mice lacking all signaling receptors for tumor necrosis factor alpha and IL-1. In a murine hepatocyte cell line, knockdown of either STAT3 or RelA by small interfering RNA inhibited cytokine induction of the APP serum amyloid A-1, demonstrating that both transcription factors were independently essential for the expression of this gene. These data suggest that during pneumonia caused by gram-negative or gram-positive bacteria, the expression of APPs in the liver depends on STAT3 activation by IL-6 and on RelA activation by early-response cytokines. These signaling axes may be critical for integrating systemic responses to local infection, balancing antibacterial host defenses and inflammatory injury during acute bacterial pneumonia.