Review
Phagocyte-specific calcium-binding S100 proteins as clinical laboratory markers of inflammation

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Abstract

The EF-hand homolog family of S100 proteins comprises the largest group of calcium-binding proteins. Within this S100 family, the phagocyte-specific calcium-binding proteins are pro-inflammatory molecules expressed and secreted by phagocytes, which play a pivotal role within the innate immune system. Although the exact biological functions of these proteins still remain to be defined in greater detail, there is evidence that they are involved in a pro-inflammatory axis associated with various inflammatory conditions. The three members of this group, S100A8, S100A9 and S100A12 are overexpressed at local sites of inflammation. High concentrations are found in synovial fluid, sputum, stool and blood plasma/serum during inflammation. Both the S100A8/S100A9 complex and S100A12 have been proven to be useful as diagnostic markers of inflammation especially in non-infectious inflammatory diseases such as arthritis, chronic inflammatory lung and bowel disease. They indicate phagocyte activation more sensitively than conventional parameters of inflammation. As a consequence, there is a strong correlation to the inflammation of various acute and chronic disorders, making these proteins sensitive parameters for the monitoring of disease activity and response to treatment in individual patients. The phagocyte-specific S100 proteins are able to indicate minimal residual inflammation, which is not detected by other diagnostic tests, and they may even be prospective markers for the outcome of patients. In this review, pro-inflammatory functions of S100 proteins and their usefulness as biomarkers of inflammation are presented.

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

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