TRANSGENIC MICE EXPRESSING RABBIT C-REACTIVE PROTEIN ARE RESISTANT TOENDOTOXEMIA

C-reactive protein (CRP), the prototypic acute-phase reactant in human s, is synthesized in liver in response to a wide variety of inflammato ry stimuli, We have generated a line of transgenic mice that express r abbit CRP from the rat phosphoenolpyruvate carboxykinase (PEPCK) promo ter in response to gluconeogenic signals. Here we show that transgenic mice expressing high levels of CRP were partially protected from a le thal challenge of bacterial lipopolysaccharide compared with littermat es in which CRP expression had been suppressed, Similar protection was observed with challenges from platelet-activating factor (PAF) and th e combination of tumor necrosis factor alpha (TNF-alpha) plus interleu kin 1 beta, but not with TNF-alpha alone, We further demonstrate that although PAF was able to bind CRP, the mechanism by which CRP provides protection probably does not involve sequestration of PAF, The biolog ically inactive precursor of PAF, lyso-PAF, also bound CRP but did not render the transgenic mice sensitive to PAF when CRP-expressing anima ls were simultaneously challenged with PAF and an excess of lyso-PAF, These results suggest that CRP functions in vivo by modulating host de fense systems.