Role of Pentraxins in Acute and Chronic Pathology

Coe, J

Abstract

We have been studying the endocrine and cytokine control of a protein synthesized in liver of Syrian hamster. This protein is homologous to two human proteins, C. reactive protein (CRP) and amyloid P component (AP), and shares 50-70% (respectively) identical amino acid sequence. These proteins also share a similar molecular configuration which is that of an oligomer of 5 identical monomer proteins noncovalently assembled as a cyclic pentamer. This family of proteins is called pentraxin, and the pentraxin of Syrian hamster is called female protein (FP). FP shares similar functional properties with CRP and AP such as Ca++ dependant Phosphoryl-choline and galactan binding, complement fixation and acute phase responsiveness. Pentraxins are widely expressed in nature, and are found even in very primitive animals. The conservative evolution of this protein family and its ubiquitous expression suggests that pentraxins are biologically important. However, a critical role for these proteins has not been found yet. In hamsters, females have 200- 300 fold more FP in serum than males, and this concentration difference reflects the different rate of hepatic synthesis by males and females. This unusual endocrine control suggests that FP may have some unusual function in the hamster which could provide information about the general function of all pentraxins. We have not found any beneficial effect from FP, and in fact high synthesis rates of FP appears to result in a shortened longevity of the female hamster. In Syrian hamsters, females normally die at an earlier age than males, (in contrast to all other mammals) and female hamsters generally die because of amyloidosis. Similar to AP in human amyloid, FP of Syrian hamsters is a constituent of amyloid, and we have shown that high serum levels of FP appear to have a primary role in the induction of amyloidosis in hamsters. The endocrine control of FP synthesis is different in other hamsters. Thus, serum FP concentration is lower in Turkish hamsters and this species, which is very closely related to Syrian hamster does not acquire amyloidosis. Turkish hamsters appear to have an FP with identical amino acid sequence to Syrian hamster FP, although serum FP levels in females are about 1/10 that found in Syrian hamsters. Control of FP synthesis in Armenian hamsters is especially different from Syrian hamster because estrogen actually down regulates Armenian FP synthesis. Exogenous estrogen also is extraordinarily toxic to livers of Armenian hamsters and chronic estrogen administration initiates in the appearance of hepatic neoplasms. Estrogen induced hepatotoxicity (cholestatic jaundice of pregnancy) and hepatic cancer are known to occur in humans, but there are no comparable animal models to study these phenomena.