Abstract Pneumonia and sepsis are integrally linked, each representing a major public health concern, and each significantly increasing the likelihood that the other will occur. However, the host mechanisms guiding this dangerous interaction remain speculative. The acute phase response is a common feature of both pneumonia and sepsis, involving robust remodeling of the hepatic transcriptome followed by mobilization of numerous liver-derived acute phase proteins, several of which are known clinical biomarkers of disease severity. The net physiological significance of these integrated acute phase changes is only beginning to be understood. We recently showed that pneumonia elicits a robust acute phase response that is functionally relevant and highly dependent on hepatocyte expression of the transcription factors NF-κB RelA and STAT3. Using hepatocyte- targeted mouse models, our preliminary studies implicate the liver as a gatekeeper that compartmentalizes infection during sepsis or pneumonia, reducing the likelihood that one will promote the other. Specifically, we now have evidence that: 1) STAT3-dependent liver responses to endotoxemia protect against pneumonia susceptibility, associated with expression of iron-regulating acute phase proteins; and 2) RelA-dependent liver responses during pneumonia protect against sepsis outcomes, including liver failure and bacteremia. Here we propose the central hypothesis that hepatocyte transcriptional responses are critical for limiting the deleterious interactions between pneumonia and sepsis. This hypothesis will be tested by pursuing the following three aims: Aim 1) Test the hypothesis that hepatocyte STAT3 activation counters sepsis-induced pneumonia susceptibility by promoting iron withdrawal and lung mucosal defense; Aim 2) Test the hypothesis that hepatocyte RelA activation counters pneumonia-induced sepsis by preventing programmed cell death, organ failure, and bacteremia; and Aim 3) Test the hypothesis that STAT3 and RelA are each essential for human hepatocytes to elicit acute phase gene programs that direct alveolar macrophage responses. Studies designed to address these aims will use a multidisciplinary approach to comprehensively determine the mechanistic basis of liver-derived protection at the interface of pneumonia and sepsis. These investigations will be the first to directly interrogate liver function in this capacity, possibly revealing important determinants of clinical outcome in patients with pneumonia or sepsis.