Human inter-α-inhibitor family in inflammation: simultaneous synthesis of positive and negative acute-phase proteins

Abstract

The inter-alpha-inhibitor (I alpha I) family encompasses four plasma proteins, namely free bikunin as well as I alpha I, pre-alpha-inhibitor (P alpha I) and inter-alpha-like inhibitor (I alpha LI). Each of the last three proteins is a distinct assembly of one bikunin chain with one or more unique heavy (H) chains designated H1, H2 and H3. The three H chains and the bikunin chain are encoded by four distinct mRNAs. These molecules and chains, as well as the corresponding mRNAs, were quantified in sera and liver biopsies from a series of patients with or without mild or severe acute infection. The decrease or increase observed for a given molecule or chain in the serum was in agreement with a similar change in the corresponding liver mRNA. In acute inflammation the H2 and bikunin chains are down-regulated and the relevant molecules (I alpha I, I alpha LI) behave as negative acute-phase proteins, whereas the H3 chain is up-regulated and the corresponding P alpha I molecule is a positive acute-phase protein. Also, P alpha I displays a higher-than-usual M(r); this is probably due to ligand binding. The H1 gene does not seem to be affected by the inflammatory condition. The quantitative changes in RNA levels seen in vivo were confirmed in vitro in the human hepatoma Hep3B cell line prior to or after induction with the acute-phase mediators interleukin-1 and/or -6. These results provide the first example in humans of positive and negative acute-phase proteins that are encoded by evolutionary related genes.

Fetuin-B, a second member of the fetuin family in mammals

“…The hepatic level of fetuin-A mRNA is down-regulated during an APR in rat [23,26] and our preliminary data indicated that the hepatic level of fetuin-B mRNA also varies following an inflammatory challenge in rat [27]. Therefore, we compared in more detail the changes of both mRNA levels of both genes in liver during an APR in rat.…”

“…Older animals were killed by cervical dislocation (mouse) or by anaesthesia with ethyl ether (rat). An acute systemic inflammation was induced in adult male rats by a single injection of bacterial lipopolysaccharides (LPS) or Freund's complete adjuvant (FCA) given intraperitoneally or turpentine oil (TO) given subcutaneously, as detailed previously [26,27].…”

“…The latter was done according to previously detailed procedures [9,26]. Northern blots were carried out and hybridized with $#P-labelled probes and the resulting signals were quantified and normalized as previously detailed [26,27].…”

“…The latter was done according to previously detailed procedures [9,26]. Northern blots were carried out and hybridized with $#P-labelled probes and the resulting signals were quantified and normalized as previously detailed [26,27]. Genomic DNA from rat or mouse was digested with various restriction enzymes and the resulting fragments were resolved by agarose gel electrophoresis, alkali-blotted and hybridized with cDNA probes under stringent conditions following standard procedures.…”

Human Inter-α-Trypsin Inhibitor Heavy Chain H3 Gene

“…It is a glycoprotein of M r 125,000 composed of one heavy chain of M r 90,000, called HC3, and one light chain of M r 16,000, bikunin carrying the glycosaminoglycan (14). The level of pre-␣-trypsin inhibitor, an acute-phase protein, rises in response to trauma and inflammation (16). In the pathological synovial fluid from human arthritis patients, HC3 is covalently bound to hyaluronan (17).…”