Serum concentration of human alpha 2 HS glycoprotein during the inflammatory process: evidence that alpha 2 HS glycoprotein is a negative acute-phase reactant.

Abstract

A B S T R A C T A nonspecific opsonin function has been ascribed to human alpha2 HS glycoprotein. Its serum level has been shown to be decreased in trauma patients. Recent studies from this laboratory revealed a heterogeneity among the final products obtained in the course of the preparation of the protein. To date, no definitive agreement existed with regard to a molecular homogeneous entity of alpha2 HS glycoprotein (Ba-alpha2 glycoproteins). The purpose of the current work was to study the variations in serum level ofalpha2 HS in patients suffering from an acute inflammatory process of bacterial etiology and to determine whether a decrease in alpha2 HS was accompanied by the appearance of fragments of this protein in the serum. A method of preparing alpha2 HS was thus developed, using an immune adsorbent as a final purification step. In an intermediary step of the preparation, alpha2 HS was found to bind zinc ions when metal chelate affinity chromatography was employed. Immunologically and physico-chemically pure alpha2 HS was obtained. The protein consists of a unique polypeptide chain of about 50,000 daltons and has a unique amino-terminal residue, alanine. However, the protein maintained its molecular integrity with difficulty, and spontaneous fragments ranging from 30,000 to <10,000 daltons were produced in some of the preparations. No major modification in the molecular structure of the protein was This work was presented in part at the Satellite Symposium "Current Concepts in Kinin Research" of the 17th International Congress of Pharmacology, Paris, July 1978.Received for publication 30 June 1978 and in revised form 16 April 1979. 1118 noted in the sera of subjects suffering from an acute inflammatory process. Serum level of alpha2 HS and alpha, antitrypsin (AT) was determined in 23 patients.When the acute-phase (AP-)reactant alpha, AT was increased (difference with normal mean >+2 or +3 SD), the sera showed a large decrease in alpha2 HS (difference with normal mean <-2 or -3 SD). The serum level of alpha2 HS, albumin, alpha2 macroglobulin, and of positive AP-reactants, orosomucoid, alpha, AT, haptoglobin, and ceruloplasmin was evaluated in a longitudinal study of seven patients. The results were submitted to a principal components analysis. Alpha2 HS showed a negative correlation with the AP-reactants alpha, AT, orosomucoid, and haptoglobin (P < 0.05) and a positive correlation with albumin (P < 0.05); these findings indicate that alpha2 HS is a negative AP-reactant. In addition, analysis of the principal components confirms the strong analogy between alpha2 HS and albumin and indicates that serum level behavior of the AP-reactants during the course of the disease closely depends on the protein studied.

The synthesis of human α‐2‐HS glycoprotein is down‐regulated by cytokines in hepatoma HepG2 cells

“…In our experiments, rhlL6 appears to be the major inducer of the decrease of AHSG synthesis in vitro. We have shown previously that the plasma concentration of AHSG is decreased during the course of an acute inflammation [5], but it was not known at the time if this was due to a decrease in synthesis or an increase in catabolism. Our present results demonstrate that AHSG belongs indeed to the group of negative acute-phase proteins and that its synthesis is regulated in a fashion similar to that of human serum albumin.…”

“…It has also the capacity to act as an opsonin [3] and to promote endocytosis [4]. Furthermore, its plasma levels decrease significantly during an inflammatory response [5]. Abbreviations: BSF-2, B-cell differentiation factor; IFN-h'2, interferon4~2; FCS, fetal calf serum; CM, conditioned medium; ITG, guanidine isothiocyanate In response to inflammation, the levels of some plasma proteins synthesized by the liver increase (positive acute-phase proteins) whereas others decrease (negative acute-phase proteins) [6].…”

cDNA Sequencing of Guinea Pig a2-HS Glycoprotein, Its Expression in Various Tissues and Acute Phase Expression

“…Protein and/or DNA sequences have been reported for human (Lee et al, 1987), cow (Dziegielewska et al, 1990), sheep and pig , rat (Ohnishi et al, 1993), mouse (Yamamoto and Sinohara, 1993;Yang et al, 1992), Mongolian gerbil (Goto et al, 1997), rabbit (Osawa et al, 1997), and Habu snake (Yamakawa and Omori-Satoh, 1992) fetuins. AHSG is also one of the few negative acute phase reactants in humans (Lebreton et al, 1979) and rats (Daveau et al, 1990), whereas fetuin is a positive acute phase protein in cattle and mice (Yang et al, 1992). To clarify the physiological role of AHSG, the structure and properties should be studied in more animal species and compared.…”

Purified Human Plasma Proteins of Unknown Function

“…Nothing is known about the amino acid sequence and the steriochemical structure. Alanine is the amino-terminal amino acid (Lebreton et al, 1979). A micro-heterogeneity for a2HS can be identified by isoelectric focusing (unpublished data).…”

“…Since it also precipitates in vitro with calcium phosphate complexes (Ashton, Hohling and Trift, 1976) and can be purified by zinc-chelat affinity chromatography (Lebreton, 1977), it can be assumed that a2HS has a metal-combining property (Lebreton, 1979) and is therefore enriched in the matrix of bone and dentine (Trift et al, 1976). Van Oss et al (1974) 2.7.…”