PARC

PARC Hisayuki Nomiyama1,* and Osamu Yoshie2 1

Department of Biochemistry, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto, 860-0811, Japan 2 Department of Bacteriology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan * corresponding author tel: +81-96-373-5065, fax: +81-96-373-5066, e-mail: [email protected] DOI: 10.1006/rwcy.2000.11008.

SUMMARY PARC is a CC chemokine that shows the highest sequence similarity to the CC chemokine MIP-1. It is expressed in lung and lymphoid tissues, and induced in monocytes by TH2-associated cytokines. In contrast to MIP-1 and most other CC chemokines, PARC is not chemotactic for monocytes and granulocytes. Since PARC attracts only a subset of T lymphocytes and is expressed in dendritic cells of lymphoid tissues, one of the functions of PARC may be the generation of primary immune responses. The human gene for PARC (SCYA18) resides in the major CC chemokine cluster at chromosome 17q11.2, while other lymphocyte-specific CC chemokine genes are located on chromosomes other than chromosome 17. The mouse ortholog of PARC might not exist in the mouse genome.

and of monocytes activated with IL-4 plus glucocorticoid (alternatively activated macrophages) (Kodelja et al., 1998), and were termed DC-CK1 and AMAC1, respectively. By exon trapping, Guan et al. (1999) identified an exon from YACs containing the CC chemokine gene cluster and isolated the PARC/MIP4 cDNA using the exon sequence as probe.

Alternative names DC-CK1 (dendritic-cell-derived CC chemokine 1) (Adema et al., 1997) MIP-4 (macrophage inflammatory protein 4) (Wells and Peitsch, 1997) AMAC-1 (alternative macrophage activation-associated CC-chemokine 1) (Kodelja et al., 1998). CCL18 (CC chemokine ligand 18) (Zlotnik and Yoshie, 1999)

BACKGROUND

Structure

Discovery

PARC is a CC chemokine containing four conserved cysteine residues, and is most similar to the CC chemokine MIP-1. Although the overall similarity between PARC and MIP-1 is very high (61% identity), the N-terminal sequences between the N-termini of the mature proteins and the first of the two adjacent cysteine residues are quite different (Figure 1). Since chemokine N-terminal sequences are of critical importance in interaction with receptors, this sequence difference may explain why PARC and MIP-1 do not share a receptor.

PARC (pulmonary and activation-regulated chemokine) was cloned and reported independently by five groups. By searching the GenBank EST database for sequences related to MIP-1, Hieshima et al. (1997) and Wells and Peitsch (1997) identified overlapping cDNAs encoding a novel chemokine that they designated PARC and MIP-4, respectively. The cDNAs encoding the same chemokine were isolated from cDNA libraries of dendritic cells (Adema et al., 1997)

1228 Hisayuki Nomiyama and Osamu Yoshie Figure 1 Amino acid comparison of the human PARC and MIP-1.

Main activities and pathophysiological roles

Cells and tissues that express the gene

As for the activities and pathophysiological roles of PARC, only the chemotactic activity and calcium mobilization are reported (see section on In vitro activities).

In spite of the close similarity to MIP-1, the expression pattern of PARC is quite different from that of MIP-1. PARC mRNA is expressed constitutively at high levels in lung and at low levels in some lymphoid tissues such as lymph node, thymus, and appendix (Hieshima et al., 1997; Guan et al., 1999), while MIP-1 is expressed mainly in spleen and PBL. By in situ hybridization, PARC mRNA is shown to be expressed in alveolar macrophages and dendritic cells in T cell areas and germinal centers of secondary lymphoid tissues (Adema et al., 1997; Hieshima et al., 1997). PARC mRNA is induced in monocytes by granulocyte± macrophage colony-stimulating factor (GM-CSF) plus IL-4 (dendritic cells) (Adema et al., 1997; Brossart et al., 1998; Kodelja et al., 1998; Sallusto et al., 1999), by lipopolysaccharide (Hieshima et al., 1997; Reape et al., 1999; Sallusto et al., 1999) and by TH2-associated cytokines such as IL-4, IL-10, and IL-13 (Kodelja et al., 1998), and the expression is inhibited by IFN (Kodelja et al., 1998). Induction of PARC expression was observed in K562, U937, and KG1 cell lines by PMA treatment (Hieshima et al., 1997; St. Louis et al., 1999).

GENE AND GENE REGULATION

Accession numbers GenBank: Human cDNA: NM_002988 Human gene: AB012113

Chromosome location By analysis of a previously constructed YAC contig (Hieshima et al., 1997) and by construction of a BAC contig (Maho et al., 1999; Tasaki et al., 1999), the human PARC gene was mapped within one of the two subclusters in the CC chemokine gene cluster at chromosome 17q11.2, and is located in the close vicinity of the MIP-1 gene.

Relevant linkages Human chromosome 17q11.2 tel±(AT744.2/SCYA4L1±LD78 /SCYA3L1±LD78 / SCYA3L2)±MIP-1 /SCYA4±MIP-1/SCYA3±PARC/ SCYA18±MPIF-1/SCYA23±Leukotactin-1/SCYA15± HCC-1/SCYA14±LEC/SCYA16±RANTES/SCYA5± M C P - 4 / S C Y A 1 3 ±I-309/SCYA1±MCP-2/SCYA8± eotaxin 1/SCYA11±MCP-3/SCYA7±MCP-1/SCYA2±cen.

PROTEIN

Accession numbers SwissProt: Human: P55774

Sequence See Figure 1.

PARC 1229

Description of protein Mature protein length: 69 molecular weight: 7855 isoelectric point: 9.39

Important homologies The most closely related chemokines to PARC are the human CC chemokine MIP-1/CCL3 (61% identity) and LD78 /CCL3L1 (60% identity). Sequence analysis suggested that the PARC gene was generated by fusion of two MIP-1-like genes with selective usage of exons (Tasaki et al., 1999).

CELLULAR SOURCES AND TISSUE EXPRESSION

Cellular sources that produce So far, there are no reports on cellular sources of PARC protein.

IN VIVO BIOLOGICAL ACTIVITIES OF LIGANDS IN ANIMAL MODELS

Normal physiological roles When PARC was injected into the peritoneal cavity of mice, both CD4+ and CD8+ T cells were attracted (Guan et al., 1999).

PATHOPHYSIOLOGICAL ROLES IN NORMAL HUMANS AND DISEASE STATES AND DIAGNOSTIC UTILITY

Role in experiments of nature and disease states Using reverse transcriptase polymerase chain reaction and in situ hybridization, gene expression for PARC was detected in human atherosclerotic plaques (Reape et al., 1999). PARC mRNA was restricted to CD68+ macrophages.

RECEPTOR UTILIZATION The receptor for PARC has not yet been identified. PARC binds to none of the following chemokine receptors: CCR1, CCR2B, CCR3, CCR4, and CCR5.

IN VITRO ACTIVITIES

In vitro findings PARC is shown to be chemotactic for both activated (CD3+) T cells and nonactivated (CD14ÿ) lymphocytes, but not for monocytes or granulocytes (Hieshima et al., 1997). Adema et al. (1997) reported that PARC preferentially attracts naõÈ ve resting T cells (CD45RA+). PARC also induced an increase in the level of intracellular free calcium in CD4+, CD8+, and naõÈ ve T cells (Guan et al., 1999).

Bioassays used To determine the target cell specificity of PARC, chemotaxis assay (Adema et al., 1997; Hieshima et al., 1997) and intracellular calcium flux measurement (Guan et al., 1999) were performed.

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