SPECIES-SPECIFIC CHANGES IN REGULATORY ELEMENTS OF MOUSE HAPTOGLOBIN GENES

Although expression of the haptoglobin (HP) as an acute phase reactant is evolutionarily conserved among mammals, there are differences amon g species with regard to the hormones required for stimulation. Using primary hepatocyte cultures, we show that in Mus caroli, as in rat, IL -1 and IL-6 are stimulatory, whereas in M. domesticus, as in humans, I L-1 response is diminished. In vivo, an acute inflammatory process inc reases hepatic HP expression in both mouse species up to 30-fold but m inimally affects the low level HP expression in the lung. To define th e species-specific differences in regulation, we isolated the hormone- responsive elements of the HP gene from the Mus species, M. domesticus , M. caroli, and M. saxicola. Functional studies in transfected hepato ma cells revealed an exceptionally strong dexamethasone response for a ll three murine HP gene elements. The IL-6 response was less prominent than in rat or human. A modest response to IL-1 was observed in M. ca roli and M. saxicola. A mouse-specific insertion of a polypurine seque nce led to a binding site for the PEA3 transcription factor in the HP gene promoter of M. domesticus and M. saxicola, but not M. caroli. The specific regulatory effects of glucocorticoid receptor, C/EBPbeta, an d Ets proteins were documented by co-transfection.