ReviewPhagocyte-specific calcium-binding S100 proteins as clinical laboratory markers of inflammation
Introduction
Calcium is a ubiquitous intracellular element with important functions as second messenger. Changes in cytosolic calcium concentrations evoke various cellular responses such as conduction of nerve impulses, muscle contraction, cell migration, cell growth, cellular differentiation and activation, changes in enzymatic activity, apoptosis and necrosis. Intracellular calcium-binding proteins are key molecules in the transduction of calcium signaling. Among the several groups of calcium-binding proteins, the EF-hand homolog family of S100 proteins comprises the largest group [1]. Another related group consists of calcium/phospholipid-binding proteins like annexins, which show calcium-dependent binding to membranes. Annexins exhibit various functions particularly important for the cellular homeostasis, but serum concentrations of annexins have not been studied systematically as markers of inflammation.
The tissue-specific pattern of S100A8 (also named calgranulin A; myeloid-related protein 8, MRP8) and S100A9 (calgranulin B; MRP14) found in phagocytes has been described in the 1980s [2], [3], [4], [5]. In addition, a signaling axis implicated in inflammatory processes has been described for S100A12 (calgranulin C; extracellular newly identified RAGE-binding protein, EN-RAGE; calcium-binding protein in amniotic fluid-1, CAAF1; p6) [6]. There is evidence that the members of the calgranulin group, i.e. the aforementioned cytosolic S100 proteins mainly expressed in phagocytes, are actively secreted and exhibit pro-inflammatory functions. Recently, receptor counterparts on various cell types involved in immune cell acquisition have been described for these proteins [6], [7].
The overexpression of S100A8 and S100A9 at sites of inflammation has been well described [3], [4], and first studies indicating a correlation of S100A8/S100A9 serum concentrations to inflammation have been published 20 years ago [8], [9]. Since then, a large body of evidence for the usefulness of S100 calcium-binding proteins as biomarkers of inflammation has been accumulated. In this review, the proposed functions of calcium-binding proteins in inflammation are presented. Data on the usefulness of these proteins as biomarkers of inflammation are summarized and discussed.
Section snippets
The S100 family of calcium-binding proteins
The first members of the S100 protein family have been described in 1965. The unfractionated mixture of previously unknown proteins purified from bovine brain was called “S100” because of its solubility in 100% ammonium sulphate solution [10]. More than a decade later this protein mixture was described more accurately as consisting of S100B and S100A1. Moreover, the structural similarity of these proteins with well known calcium-binding proteins of the EF-hand type such as calmodulin was
Pro-inflammatory effects of phagocyte-specific S100 proteins
Three phagocyte-specific S100 proteins comprise the group of calgranulins. The three members of this protein group, S100A8, S100A9 and S100A12 are characterized by a unique expression pattern, with prevalence in cells of myeloid origin. The heterodimer of S100A8 and S100A9 was also known as cystic fibrosis antigen [5], [41]. This complex was also called “leukocyte protein L1” and is still designated as calprotectin by some research groups [42], [43]. Taken together, the calgranulins contribute
Infections
The stepwise elucidation of the structure, expression and function of the phagocyte-specific S100 proteins has continuously been accomplished by studies on plasma/serum concentrations under normal and pathologic conditions. These studies used semi-quantitative or quantitative ELISA as a specific method for the detection of distinct S100 proteins. In 1984, Sander et al. [8] reported of leukocyte L1 protein, consisting of the S100A8/S100A9 complex, as a marker of inflammation in febrile
Conclusions
The usefulness of phagocyte-specific calcium-binding proteins of the S100 family as diagnostic markers of inflammation has been demonstrated in numerous clinical studies. S100A8/S100A9 and S100A12 are pro-inflammatory molecules expressed and secreted by early recruited phagocytes, and they seem to play a pivotal role in innate immune responses. The exact biological functions and the feasibility as a target for anti-inflammatory therapies remain to be studied in greater detail. However, these
References (146)
- et al.
RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides
Cell
(1999) A soluble protein characteristic of the nervous system
Biochem. Biophys. Res. Commun.
(1965)- et al.
Ions binding to S100 proteins: I. Calcium- and zinc-binding properties of bovine brain S100 alpha alpha, S100a (alpha beta), and S100b (beta beta) protein: Zn2+ regulates Ca2+ binding on S100b protein
J. Biol. Chem.
(1986) - et al.
Binding of Ca2+ and Zn2+ to human nuclear S100A2 and mutant proteins
J. Biol. Chem.
(1998) - et al.
S100A16, a ubiquitously expressed EF-hand protein which is up-regulated in tumors
Biochem. Biophys. Res. Commun.
(2004) - et al.
Analysis of the MRP8–MRP14 protein-protein interaction by the two-hybrid system suggests a prominent role of the C-terminal domain of S100 proteins in dimer formation
J. Biol. Chem.
(1999) - et al.
Calcium-induced noncovalently linked tetramers of MRP8 and MRP14 are confirmed by electrospray ionization-mass analysis
J. Am. Soc. Mass. Spectrom.
(2000) - et al.
S100A12 is expressed exclusively by granulocytes and acts independently from MRP8 and MRP14
J. Biol. Chem.
(1999) - et al.
Association of S100B with intermediate filaments and microtubules in glial cells
Biochim. Biophys. Acta
(1998) - et al.
S100B, a neurotropic protein that modulates neuronal protein phosphorylation, is upregulated during lesion-induced collateral sprouting and reactive synaptogenesis
Brain Res.
(1998)