The
acute-phase response is characteristic of perhaps all
infections, including
bacterial pneumonia. In conjunction with the
acute-phase response, additional
biological pathways are induced in the liver and are dependent on the
transcription factors STAT3 and NF-κB, but these responses are poorly understood. Here, we demonstrate that
pneumococcal pneumonia and other severe
infections increase expression of multiple components of the cellular secretory machinery in the mouse liver, including the endoplasmic reticulum (ER) translocon complex, which mediates protein translation into the ER, and the coat
protein complexes (
COPI and COPII), which mediate vesicular transport of
proteins to and from the ER. Hepatocyte-specific mutation of STAT3 prevented the induction of these secretory pathways during
pneumonia, with similar results observed following pharmacological activation of ER stress by using
tunicamycin. These findings implicate STAT3 in the unfolded protein response and suggest that STAT3-dependent optimization of secretion may apply broadly.
Pneumonia also stimulated the binding of phosphorylated STAT3 to promoter regions of secretion-related genes in the liver, supporting a direct role for STAT3 in their transcription. Altogether, these results identify a novel function of STAT3 during the
acute-phase response, namely, the induction of secretory machinery in hepatocytes. This may facilitate the processing and delivery of newly synthesized loads of
acute-phase proteins, enhancing innate immunity and preventing liver injury during
infection.