Review
α1-Microglobulin: a yellow-brown lipocalin

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Abstract

α1-Microglobulin, also called protein HC, is a lipocalin with immunosuppressive properties. The protein has been found in a number of vertebrate species including frogs and fish. This review summarizes the present knowledge of its structure, biosynthesis, tissue distribution and immunoregulatory properties. α1-Microglobulin has a yellow-brown color and is size and charge heterogeneous. This is caused by an array of small chromophore prosthetic groups, attached to amino acid residues at the entrance of the lipocalin pocket. A gene in the lipocalin cluster encodes α1-microglobulin together with a Kunitz-type proteinase inhibitor, bikunin. The gene is translated into the α1-microglobulin-bikunin precursor, which is subsequently cleaved and the two proteins secreted to the blood separately. α1-Microglobulin is found in blood and in connective tissue in most organs. It is most abundant at interfaces between the cells of the body and the environment, such as in lungs, intestine, kidneys and placenta. α1-Microglobulin inhibits immunological functions of white blood cells in vitro, and its distribution is consistent with an anti-inflammatory and protective role in vivo.

Introduction

The first description of the lipocalin protein superfamily was based on the sequence homology between retinol-binding protein, β-lactoglobulin and α1-microglobulin [1]. Thus, α1-microglobulin (α1m) was one of the original three lipocalins.

α1m was first isolated from human urine by Ingemar Berggård and co-workers [2]. It was described as a plasma glycoprotein with a molecular mass of 26 kDa ([3]; reviewed in [4]). It has later been designated other names, e.g. protein HC [5] and α1-microglycoprotein [6]. α1m has many intriguing properties. For instance, it carries a set of chromophores which gives the protein a yellow-brown color and an extremely heterogeneous charge. It also has a pronounced tendency to associate covalently with many plasma proteins forming different high molecular weight complexes in different species. Furthermore, it is encoded by a gene which is unique because it encodes both α1m and another protein, bikunin, which has no other known relation to α1m than the co-synthesis. α1m and bikunin are translated in the liver cell as a continuous precursor protein which is cleaved before the two proteins are secreted to the blood separately.

α1m is broadly distributed in the animal kingdom. With the exception of the central nervous system, the protein is found in most, if not all tissues including blood. α1m homologues have been described in mammals, birds, amphibians and fish. The exact function of the protein is not known. However, it has many immunological, mostly immunosuppressive properties. It is therefore possible that α1m is involved in immunoregulation. In this review we will summarize the structural and biochemical properties of α1m, its tissue distribution in normal and pathological conditions and its immunological properties.

Section snippets

Peptide chain

The full sequence of human α1m was first reported by Kaumeyer et al. [7]. The protein was found to consist of 183 amino acid residues. Since then ten additional α1m cDNAs have been isolated and sequenced, including cDNA from seven mammals [8], [9], [10], [11], [12], [13], one amphibian [14], and two fishes [16], [15] (Fig. 1). The length of the peptide chain of α1m differs slightly among species, mainly due to variations in the C-terminus. Alignment comparisons of the different deduced amino

Co-synthesis with bikunin

α1m is synthesized in the liver [31], [32], [33]. The sequence of liver α1m-cDNA shows that it encodes not only α1m, but also bikunin, another plasma protein [7] (Fig. 4). Bikunin is the small, active subunit of protein/carbohydrate complexes that together constitute the so-called inter-α-inhibitor family. Its members are extracellular proteins that exhibit proteinase inhibitor activity [34] and are important factors of extracellular matrix [35]. Bikunin is modified intracellularly by

Presence in liver, plasma and kidneys

Early quantitative tissue distribution studies revealed liver, blood plasma, and kidney as major sites of α1m localization [51]. This reflects the major phases of the metabolism of the protein (Fig. 5A,B). The liver is a site of synthesis of α1m in all species studied (see above) with the hepatocyte being the predominant site of α1m synthesis in adult tissues [33], [52]. After secretion to blood, the protein exists in free form as well as in a variety of high molecular weight complexes (see

Plasma

Determination of the α1m concentration in human plasma or serum is complicated by the presence of different forms of the protein (see above). Consequently, reports on normal α1m concentrations in human plasma/serum have varied widely. Several investigators have measured free α1m and IgA-α1m separately in normal serum [56], [72], [73], [74]. For example, DeMars et al. [74] found a mean concentration of 33 mg/l for free α1m and 248 mg/l for IgA-α1m, corresponding to a molar ratio of approx. 1:1.

Biological effects

α1m inhibits central events of the immune response in vitro (Table 1). The antigen-induced cell division of peripheral blood lymphocytes (PBL) was inhibited by α1m [94], [95]. The effects were species independent, i.e. similar effects on human cells were obtained with human, rat, rabbit or guinea pig α1m [96]. It was also shown that the antigen-induced interleukin-2 (IL-2) production by mouse T helper cell hybridomas was inhibited by human α1m [97]. Normal plasma concentrations of α1m gave

Heterologous expression

As it has proven impractical to perform large-scale purifications of α1m from most organisms, vectors for heterologous expression have been constructed. The protein has been successfully expressed and purified using both Escherichia coli and the baculovirus/insect cell line system. The two systems will be briefly described below as well as the differences between recombinant α1m and α1m obtained from the original source. High-yield in vitro expression has also allowed production of large

Conclusion

Although α1m has demonstrated immunosuppressive properties, its exact biological function is unknown despite more than 25 years of research. However, many unusual and intriguing properties of the protein have been revealed during this time. The phylogenetic and tissue distribution of α1m, for example, points to a generally important function. The ancestral fusion of the α1m and bikunin genes, and the evolutionary conservation of the construction, indicate that this conferred important

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