S100A12 Zheng Yang and Carolyn L. Geczy* Cytokine Research Unit, School of Medical Sciences, The University of New South Wales, Kensington, New South Wales 2052, Australia * corresponding author tel: 61-2-9385-1599, fax: 61-2-9385-1389, e-mail:
[email protected] DOI: 10.1006/rwcy.2001.1208. Chapter posted 5 November 2001
SUMMARY
BACKGROUND
S100A12 (calgranulin C) is a member of the S100 multigene family of calcium-binding proteins implicated in the Ca2-dependent regulation of a variety of intracellular activities including protein phosphorylation, kinase activities, cell proliferation and differentiation, the dynamics of cytoskeletal rearrangement and structural organization of membranes, intracellular Ca2 homeostasis, inflammation, and in protection from oxidative cell damage (Donato, 1999, 2001). S100A12 (A12) is constitutively expressed in neutrophils (Dell'angelica et al., 1994) and is induced in mononuclear cells and the Jurkat T cell line (Hofmann et al., 1999; Yang et al., 2001). A12 is a ligand for the receptor for advanced glycosylation endproducts (RAGE) and mediates NF-B-dependent activation of monocytes and endothelial cells through RAGE binding (Hofmann et al., 1999). A12 is a potent chemoattractant for monocytes (Hofmann et al., 1999; Yang et al., 2001) and the high levels found in synovial fluid of rheumatoid patients (Yang et al., 2001) and in atherosclerotic lesions of apo E-null mice (Kislinger et al., 2001) may contribute to monocyte recruitment in these conditions. A12 has been associated with host responses to Onchocerca volvulus infection (Marti et al., 1996), and the protein has filariacidal and filariastatic activities (Gottsch et al., 1999a). A12, reported as cornealassociated antigen, was identified as the target for autoantibodies in Mooren's ulcer (Gottsch et al., 1995; Liu and Gottsch, 1996) and is upregulated by proinflammatory cytokines in corneal fibroblasts (Gottsch et al., 1999b). A12 is expressed by keratinocytes in psoriasis lesions (Mirmohammadsadegh et al., 2000) and has been associated with cell growth arrest of epithelial cells (Hitomi et al., 1998).
Discovery
Cytokine Reference
S100A12 is constitutively expressed in neutrophils and was first discovered as a result of an effort to identify mediators of calcium signaling in porcine granulocytes (Dell'angelica et al., 1994). The amino acid sequence contains two conserved calcium-binding EF hands (i.e. helix-loop-helix) typical of the S100 type (Kligman and Hilt, 1988), which, together with its size and other structural homologies, allowed assignment to the S100 protein family. Human A12 was first detected in cytosol of resting neutrophils which translocates to cytoskeletal and membrane structures after calcium-dependent activation (Guignard et al., 1995). The protein and gene from neutrophils were subsequently characterized by different laboratories (Ilg et al., 1996; Marti et al., 1996; Wicki et al., 1996; Yamamura et al., 1996). Bovine A12 in corneal stromal extracts was identified as the target for autoantibodies found in serum from patients with Mooren's ulcer (Liu and Gottsch, 1996). A12 is abundant in bovine amniotic fluid (Hitomi et al., 1996). During reduction of sulfate to sulfite in neutrophils, rabbit A12 reacts with sulfite to form an S-sulfo-protein at its unique cysteine residue and A12 was proposed to act as a sulfite-carrier protein (Yang et al., 1996).
Alternative names A12 was initially named calgranulin C because of its high amino acid sequence homology to S100A8 and S100A9 (i.e. calgranulin A and calgranulin B) and its constitutive expression in neutrophils (Dell'angelica et al., 1994). It has also been referred to as p6 (protein of 6 kDa) (Guignard et al., 1995), CGRP
Copyright # 2001 Academic Press
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Zheng Yang and Carolyn L. Geczy
(calgranulin-related protein) (Marti et al., 1996), CAAF1 (calcium-binding protein in amniotic fluid 1) (Hitomi et al., 1996), CO-Ag (cornea-associated antigen) (Liu and Gottsch, 1996) and EN-RAGE (extracellular newly identified RAGE-binding protein) (Hofmann et al., 1999). According to the proposed new nomenclature for S100 proteins (Schafer et al., 1995), it has been assigned as S100A12.
Structure The protein has 91 amino acids with a molecular weight of 10.5 kDa, depending on species. Characteristic of the S100 protein family, A12 has two highly conserved EF-hand calcium-binding domains, one of high affinity, and the other of low affinity, each flanked by hydrophobic helices. A zinc-binding site is located at the C-terminal end. The two calcium-binding domains are separated by a hinge region, a highly divergent domain within members of this family, linked to functional heterogeneity (Kligman and Hilt, 1988; Lackmann et al., 1993). Under physiological conditions, A12 is predicted to form noncovalent dimers (Moroz et al., 2001).
Main activities and pathophysiological roles A12 induces migration of monocytes at picomolar levels; its chemotactic effects on neutrophils are less potent (Yang et al., 2001). It is induced in monocytes by LPS and TNF (Yang et al., 2001). A12 was identified as a ligand for RAGE (Hofmann et al., 1999). Activation of monocytes and endothelial cells, at least partially mediated through RAGE binding, induces secretion of proinflammatory cytokines from mononuclear cells and expression of adhesion molecules on endothelial cells (Hofmann et al., 1999). In models of delayed-type hypersensitivity and colitis, administration of soluble RAGE, antiRAGE or anti-A12 substantially suppresses leukocyte
recruitment and inflammation (Hofmann et al., 1999). In rheumatoid arthritis patients, high levels of A12 are found in synovial fluid and in neutrophils in the perivascular region of the synovium as well as in some macrophages at the synovial lining layer (Yang et al., 2001); and in aortas and kidneys of diabetic apoE-null mice, A12 and A12-expressing inflammatory cells are elevated (Kislinger et al., 2001), suggesting a role in leukocyte recruitment. A12 has been associated with host responses to Onchocerca volvulus infection (Marti et al., 1996), and has filariacidal and filariastatic activities (Gottsch et al., 1999a). A12, reported as corneal-associated antigen, was identified as the target for autoantibodies found in plasma of patients with Mooren's ulcer (Liu and Gottsch, 1996). It is upregulated by TNF and IL-1 in corneal fibroblasts (Gottsch et al., 1999b). Mooren's ulcer is also associated with filarial infections (Majekodunmi, 1980). A12-mediated microfilarial immobilization in the cornea might cause local inflammation and contribute to the pathogenesis of these corneal diseases. A12 is expressed by keratinocytes in psoriatic lesions and may be associated with proliferation (Mirmohammadsadegh et al., 2000). On the other hand, A12 is expressed in differentiating esophageal epithelial cells but not in immature proliferating cells (Hitomi et al., 1998) and its role in differentiation and proliferation is unclear.
GENE AND GENE REGULATION
Accession numbers Human cDNA: D83664, X97859 Human gene: D83657, X98288, X98289, X98290 Bovine cDNA: D49548, AF011757 Rabbit cDNA: AF091848
Sequence Human A12 cDNA sequence is shown in Figure 1.
Figure 1 cDNA sequence of human S100A12 (the coding region is shown by uppercase letters). 1 61 121 181 241 301 361 421
gctgtagctc CTTGAAGAGC CATTTTGACA ACCATCAAGA AATCAAGATG GCTGCCCATT tgtcctcaat agagttaata
cacattcctg ATCTGGAGGG CCCTCTCTAA ATATCAAAGA AACAGGTCGA ACCACACCCA gagggtcttt aacacactca
tgcattgagg AATTGTCAAT GGGTGAGCTG TAAAGCTGTC CTTTCAAGAA CAAAGAGtag tctttccctc cgaaaaaaaa
ggttaacatt ATCTTCCACC AAGCAGCTGC ATTGATGAAA TTCATATCCC gtagctctct accaaaaccc aaaaaaaaaa
aggctgggaa AATACTCAGT TTACAAAGGA TATTCCAAGG TGGTAGCCAT gaaggctttt agccttgccc a
gatgACAAAA TCGGAAGGGG GCTTGCAAAC CCTGGATGCT TGCGCTGAAG tacccagcaa gtggggagta
S100A12 3
Chromosome location The human gene is localized on chromosome 1q21 within the S100 gene cluster (Wicki et al., 1996; Yamamura et al., 1996).
Relevant linkages Most genes encoding S100 proteins have striking similarities with respect to intron±extron organization. A12 consists of three exons divided by two introns; exon 1 encodes the 50 -untranslated region; each of the two EF-hand motifs are separately encoded by exons 2 and 3 (Wicki et al., 1996; Yamamura et al., 1996). A12 cDNA has highest homology with S100A9, especially within the N-terminal motif and the EF-hand regions (Yamamura et al., 1996). A12 is localized nearest to S100A9, sandwiched between S100A8 and S100A9 in chromosome 1q21 (Wicki et al., 1996). Because of the overlapping distribution of the three proteins in myeloid and epithelial cells, as well as their high structural similarities, it is suggested that transcriptional regulation of these genes may be similar and may employ a common regulatory region within the cluster (Wicki et al., 1996).
Regulatory sites and corresponding transcription factors No in-depth study reported. Two putative AP-1 and three AP-2 elements upstream of the transcription initiation site have been identified for human A12 (Yamamura et al., 1996).
Cells and tissues that express the gene See Table 1. Northern analysis has detected the mRNA in spleen and thymus and in neutrophils and some macrophages in the lung, liver and spleen (Hitomi et al., 1996; Yamamura et al., 1996). A12 is constitutively expressed in the neutrophils and comprises approximately 2% of total cytosolic protein (Dell'angelica et al., 1994), but is not present in resting lymphocytes or monocytes (Vogl et al., 1999; Robinson and Hogg, 2000). A12 is induced in monocytes upon activation by LPS and TNF (Yang et al., 2001). Surface receptor crosslinking of peripheral mononuclear cells and Jurkat T cell line with anti-CD3/CD28 also induced A12 (Hofmann et al., 1999).
Table 1 Cells and tissues that express S100A12 Organ
Cell types
References
Spleen Thymus
Neutrophils, macrophages
Hitomi et al., 1996; Yamamura et al., 1996
Liver
Neutrophils, macrophages
Hitomi et al., 1996
Lung
Neutrophils, macrophages, epithelial cells
Hitomi et al., 1996; Hofmann et al., 1999; Yamamura et al., 1996
Esophagus
Epithelial cells, Squamous cells
Hitomi et al., 1996
Placenta Umbilical cord
Squamous cells
Hitomi et al., 1996
Skin
Keratinocytes
Hitomi et al., 1996; Mirmohammadsadegh et al., 2000
Eye (cornea, stroma)
Epithelial cells, Squamous cells
Hitomi et al., 1996; Liu and Gottsch, 1996
Brain (Corpora amylacea)
Macrophages
Hoyaux et al., 2000
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Bovine esophagus, eye, skin, umbilical cord, and placenta are A12-positive (Hitomi et al., 1996). Esophageal epithelial cells undergoing differentiation express A12 whereas proliferating cells apparently do not (Hitomi et al., 1998). On the other hand, overexpression of A12 has been reported in lesional psoriasis characterized by continued proliferation of keratinocytes, but not in normal skin (Mirmohammadsadegh et al., 2000). A12 was detected in stroma of Mooren's ulcer, rejected corneal grafts, and in corneas with previous bacterial infections. IL-1 and TNF induce A12 in cultured corneal keratocytes (Gottsch et al., 1999b). Along with other S100 proteins, A12 was detected in activated macrophages within the Corpora amylacea of normal human brain (Hoyaux et al., 2000).
PROTEIN
Accession numbers Human: P80511, JC4712 Bovine: P79105 Porcine: P80310 Rabbit: AAC61770
S100 protein family, each flanked by hydrophobic helices. The two calcium-binding domains are separated by a hinge linker region. The linker region and the C-terminal domains are structurally highly divergent among the S100 protein family and are proposed to be responsible for specificity of target recognition (Kligman and Hilt, 1988). Under physiological conditions, A12 is predicted to form homodimers in an asymmetric unit, with interfaces between the subunits composed mainly of the hydrophobic region (Moroz et al., 2000). In addition to binding calcium, A12 binds zinc with high affinity. The zinc-binding site, a His-X-X-X-His motif, is located at the C-terminal end. Zinc binding profoundly increases the calcium-binding affinity of the protein (Dell'angelica et al., 1994). Human A12, unlike most other S100 proteins, contains no Cys or Met residues, indicating potential resistance to oxidation. Oxidation of numerous chemoattractants can cause loss of function (Clark, 1982; Harrison et al., 1999) whereas A12 may remain active in situations such as inflammatory reactions, where cellular oxidants are generated.
Discussion of crystal structure
Sequence Sequences of human, bovine, porcine, and rabbit A12 are shown in Figure 2.
Description of protein A12 is a molecule of 91 amino acids with a molecular weight of 10.5 kDa. It has two highly conserved EF-hand calcium-binding sites characteristic of the
Comparison of the crystal structure of A12 with crystal structures of other S100 proteins predicts residues responsible for intra- and intermolecular interactions (Moroz et al., 2001). A12, like all S100 proteins, forms a hydrophobic core that significantly influences its calcium-binding properties. The dimer is stabilized by hydrophobic contact between antiparallel helices of the two subunits. Sequence and structure comparisons between members of the S100 family predict that the target-binding regions in A12 are formed by the linker region and the C-terminal residues of one subunit and the N-terminal residues of another subunit of the homodimer (Moroz et al., 2001).
Figure 2 Amino acid sequence of human, bovine, porcine and rabbit S100A12. Human Bovine Porcine Rabbit
TKLEEHLEGIVNIFHQYSVRKGHFDTLSKGELKQLLTKELANTIKNIKDK TKLEDHLEGIINIFHQYSVRVGHFDTLNKRELKQLITKELPKTLQNTKDQ TKLEDHLEGIINIFHQYSVRLGHYDTLIKRELKQLITKELPNTLKNTKDQ TKLEDHLEGIINIFHQYSVRTGHYDTLSKCELKKLITTELVNTIKNTKDQ
Human Bovine Porcine Rabbit
AVIDEIFQGLDANQDEQVDFQEFISLVAIALKAAHYHTHKE PTIDKIFQDLDADKDGAVSFEEFVVLVSRVLKTAHIDIHKE GTIDKIFQNLDANQDEQVSFKEFVVLVTDVLITAHDNIHKE ATVDRIFRDLDEDGDHQVDFKEFLSLLASVLVTAHENIHKE
S100A12 5
Important homologies Human A12 has high homology with other S100 proteins, the closest being S100A9 (47%) and S100A8 (40%). Despite similarities in cellular expression, and simultaneous calcium-dependent translocation from cytosol to cytoskeletal and membrane structures in activated neutrophils (Guignard et al., 1995), recent studies indicate that A8, A9, and A12 have distinct functions. Unlike the regularly reported formation of noncovalent heterodimers between A8 and A9, direct protein±protein interactions between A12 and A8 or A9 have not been reported (Robinson and Hogg, 2000; Vogl et al., 1999). In addition, A9, but not A12, is expressed in normal adult skin, and in psoriatic tissues (Robinson and Hogg, 2000) and the proteins are differentially expressed in rheumatoid synovium (Yang et al., 2001). Functionally, A12 is more akin to a subset of chemotactic S100 proteins. S100A2 and S100A7 are chemotactic for eosinophils (Komada et al., 1996) and T cells and neutrophils (Jinquan et al., 1996) respectively. A12 is chemotactic for monocytes and neutrophils, but not lymphocytes (Hofmann et al., 1999; Yang et al., 2001). The murine homolog of A8 is chemotactic for similar cell types as A12, but this activity is not shared by its human counterpart (Lackmann et al., 1993). Moreover, the kinetics of leukocyte recruitment elicited by murine A8 and human A12 in vivo are strikingly similar, suggesting that they may be functional homologs, despite the relatively low sequence homology between the two proteins (33% identity). No murine A12 has been found in EST databases, in the genome, or by us using protein separation of various cell types known to express A12 in other species.
Posttranslational modifications No posttranslational modifications of A12 have been reported, except for the formation of S-sulfoderivative on Cys30 of the rabbit protein (Yang et al., 1996). The lack of Cys residues in all other species of A12 known to date indicates that this property may be exclusive to the rabbit protein.
Eliciting and inhibitory stimuli, including exogenous and endogenous modulators A12 expression in monocytes is induced by LPS in a time- and dose-dependent manner (Yang et al., 2001). Infusion of LPS into mice caused time-dependent release of A12 into plasma (Hofmann et al., 1999). A12 is induced in monocytes by TNF but not by IL-1 (Yang et al., 2001). Receptors crosslinking of peripheral blood mononuclear cells and the Jurkat T cell line with anti-CD3/CD28 induced A12 (Hofmann et al., 1999). In cultured corneal keratocytes, A12 is induced by IL-1 and TNF (Gottsch et al., 1999b).
RECEPTOR UTILIZATION A12 may at least partially mediate its proinflammatory activity through ligation of RAGE, a multiligand member of the immunoglobulin superfamily. Its expression is upregulated at sites of diverse pathologies (Hofmann et al., 1999; Schmidt et al., 2000). Soluble RAGE (sRAGE) or anti-RAGE significantly reduced A12-induced chemotaxis of monocytes and upregulation of ICAM and VCAM in HUVEC in vitro. Macrophages overexpressing RAGE released IL-1 and TNF when activated with A12 and these were significantly reduced when cells were transfected with a RAGE-tail deletion construct. Intracellular signaling pathways involve NF-B activation. Administration of A12 in vivo increased expression of VCAM and influx of leukocytes which is partially suppressed by sRAGE or anti-RAGE (Hofmann et al., 1999). RAGE is a promiscuous receptor in that binding to A12 is not unique. Other ligands include some S100 proteins, advanced glycation end products (AGE), amyloid peptide and amphoterin. Ligation of S100B and S100A1 with RAGE on neuroblastoma cells causes neurite outgrowth and activation of NF-B, causing trophic or toxic effects, depending on S100B concentration. Similar effects were observed with amphoterin (Huttunen et al., 2000).
CELLULAR SOURCES AND TISSUE EXPRESSION
IN VITRO ACTIVITIES
Cellular sources that produce
In vitro findings
See Cells and tissues that express the gene and Table 1.
See Table 2.
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Table 2 In vitro activities of S100A12 A12 activities in vitro
References
Chemotactic for neutrophils and monocytes
Hofmann et al., 1999; Yang et al., 2001
Induces actin polymerisation and calcium influx in monocytes
Yang et al., 2001
Induces expression of VCAM and ICAM on endothelial cells
Hofmann et al., 1999
Induces secretion of IL-1 and TNF in monocytes
Hofmann et al., 1999
Overexpression in epithelioid-carcinoma cells caused cell growth arrest
Hitomi et al., 1998
Exhibits filariacidal and filariastatic activity against filarial parasites
Gottsch et al., 1999a
Binds autoantibodies of Mooren's ulcer
Liu and Gottsch, 1996
Regulatory molecules: Inhibitors and enhancers See Eliciting and inhibitory stimuli.
Bioassays used A12-induced monocyte migration can be measured in 48-well microchemotaxis chambers (Hofmann et al., 1999) or in 96-well plate chemotaxis chambers (Yang et al., 2001) fitted with polycarbonate membranes. A12-induced cell activation can be monitored by measuring cystolic Ca2 flux in monocytoid cells loaded with the fluorescent probe, Fluo-3 (Yang et al., 2001). Human A12 protein levels can be measured by sandwich ELISA (Hitomi et al., 1998; Yang et al., 2001).
IN VIVO BIOLOGICAL ACTIVITIES OF LIGANDS IN ANIMAL MODELS
Normal physiological roles Administration of A12 induces migration of leukocytes and localized inflammation (Hofmann et al., 1999; Yang et al., 2001), indicating a proinflammatory role. In models of delayed-type hypersensitivity and colitis, administration of soluble RAGE, antiRAGE or anti-A12 substantially suppress leukocyte recruitment and inflammation (Hofmann et al., 1999). In inflammatory tissues such as human rheumatoid arthritis synovium (Yang et al., 2001) and in diabetic aortas and kidneys from ApoE-null mice (Kislinger et al., 2001), elevated A12 levels support a role in leukocyte recruitment.
Like proteins of the S100 family, A12 lacks a classical signal peptide sequence for secretion although there is ample evidence of their extracellular function. Its secretion mechanism may involve a novel tubulin-dependent pathway reported for S100A8/9 (Rammes et al., 1997). Although there are no reports of its secretion into supernatants of activated cells in culture, A12 was found in serum of LPS-infused mice (Hofmann et al., 1999). Serum levels of A12 in patients with inflammatory disease have not been tested to date. Neutrophil-derived A12 was extracted from Onchocerca volvulus-infected nodules, suggesting an association with host responses to Onchocerca volvulus infection (Marti et al., 1996). A12 was identified as a target for autoantibodies in found in serum from patients with Mooren's ulcer (Gottsch et al., 1995; Liu and Gottsch, 1996), a condition associated with filarial infections (Majekodunmi, 1980). It was suggested that A12 attached to filarial surface proteins may lead to the exposure of pathogenic A12 epitopes, causing a hyperreactive autoimmune response characteristic of Mooren's ulcer. On the other hand, A12 has filariacidal and filariastatic activities in vitro (Gottsch et al., 1999a). A12-mediated microfilarial immobilization in the cornea might cause local inflammation and contribute to the pathogenesis of these corneal diseases. A12 may be involved in proliferation of keratinocytes. It is not detected in normal skin but is overexpressed in psoriatic lesions (Mirmohammadsadegh et al., 2000). High levels of A12 are found in amniotic fluid although its role in embryogenesis remains unclear (Hitomi et al., 1996).
Species differences Leukocyte recruitment and activation activities were demonstrated with human and bovine A12. No
S100A12 7 function is reported for porcine A12. Rabbit A12 is the only known A12 with a single Cys residue and was proposed to act as a sulfite-carrier protein (Yang et al., 2001). No murine or rat homologs have been structurally identified or defined. On the other hand, A12 was detected in murine plasma following LPS infusion into mice, and delayed-type hypersensitivity and colitis in mice was inhibited by anti-bovine A12 (Hofmann et al., 1999). Expression in inflammatory cells in aorta and kidney of diabetic apoE-null mice was reported using an antibody against anti-bovine A12 (Kislinger et al., 2001). Because of the high sequence homologies between various S100 proteins, specificities of antibodies and antagonists are key to defining the expression and activities of these molecules. Many anti-S100 antibodies crossreact with common epitopes on other S100 proteins, and the specificities of reagents used in the murine studies have not been published.
Endogenous inhibitors and enhancers Inhibitors: sRAGE; picomolar levels detected in plasma of normal and diabetics human and animals (Schmidt et al., 2000) Enhancers: TNF , IL-1
PATHOPHYSIOLOGICAL ROLES IN NORMAL HUMANS AND DISEASE STATES AND DIAGNOSTIC UTILITY The suppression of leukocyte recruitment and inflammation by anti-A12 and sRAGE (Hofmann et al., 1999) suggests that strategies to neutralize A12 function may limit monocyte recruitment in inflammatory diseases.
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