HCC-4/CCL16

4 Pages·2001·0.079 MB·English

by  Hedrick J.A.

HCC-4/CCL16
Joseph A. Hedrick
Human Genome Research, Schering-Plough Research Institute, 2015 Galloping Hill Road,
Kenilworth, NJ 07033, USA
corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2001.1124.
Chapter posted 5 November 2001
SUMMARY Alternative names
HCC-4(hemofiltrateCCchemokine-4)(Hedricketal., HCC-4 is also known as LEC (liver-expressed
1998),alsocommonlyknownasLEC(liver-expressed chemokine)(Shoudaiet al., 1998),LMC (lymphocyte
chemokine), belongs to a group of macrophage and monocyte chemoattractant) (Youn et al., 1998),
inflammatory protein (MIP)-related (cid:12) chemokines LCC-1(liverCCchemokine1)(Yangetal.,2000),and
and is most similar (38% identity) to HCC-1. HCC-4 NCC-4 (novel CC chemokine4) (Naruse et al., 1996,
isreportedtobechemotacticforbothmonocytesand Shoudai et al., 1998). According to the recently
lymphocytes(Hedrick etal., 1998,Younetal.,1998), proposed chemokine nomenclature (Zlotnik and
but is less potent than most other chemokines. More Yoshie, 2000), HCC-4 is now designated CCL16.
recently Howard et al. (2000) reported HCC-4 to be
effective in generating cell adhesion, with a potency
Structure
comparable to RANTES in the assay employed. This
suggests that regulation of adhesion may, in fact, be
the primary biologic function of HCC-4 (Howard HCC-4 possesses a primary amino acid sequence
et al., 2000). Cross-desensitization experiments have typicalof(cid:12) chemokines.TheCterminusissomewhat
shown that HCC-4 shares at least one receptor with extended(about20aminoacids)comparedwithmost
RANTES (Hedrick et al., 1998) and more recently chemokines and contains a single consensus site for
HCC-4 has been reported to interact with two N-terminal glycosylation. The precise sequence and
receptors, CCR1 and CCR8 (Howard et al., 2000). molecular weight of the mature HCC-4 protein has
The expression pattern of HCC-4 at the level of not been experimentally determined.
mRNA includes the liver, but other sites are
controversial, as discussed below.
Main activities and
pathophysiological functions
BACKGROUND
HCC-4 is reportedly chemotactic for a variety of
Discovery
leukocytes including T cells and monocytes, however
the concentrations required for maximal effect in
HCC-4wasoriginallyreportedasanuncharacterized, in vitro microchemotaxis assays are 10–100 times
chemokine-like gene present in a chemokine gene higher than those typically observed with other
cluster on chromosome 17q11.2 (Naruse et al., 1996). chemokines (Hedrick et al., 1998, Youn et al., 1998,
Several groups subsequently reported cloning of the Howard et al., 2000). Surprisingly, HCC-4 is more
cDNA for human HCC-4 (Hedrick et al., 1998, effective in generating cell adhesion than chemotaxis
Shoudai et al., 1998, Youn et al., 1998) and in vitro anditseffectsinthisregardwerecomparabletothose
characterization of the protein’s biological activity of RANTES (Howard et al., 2000). In addition to its
(Hedrick et al., 1998, Youn et al., 1998) regulation of chemotaxis and adhesion, HCC-4 has
CytokineReference Copyright#2001AcademicPress
2 Joseph A. Hedrick
been reported to possess myelosuppressive activity Cells and tissues that express
comparable to that of MIP-1(cid:11) (Youn et al., 1998).
the gene
GENE AND GENE REGULATION The expression of HCC-4 is somewhat controversial
as different groups have reported either liver-specific
Accession numbers expression or more ubiquitous expression. Hedrick
et al. (1998) reported that a small, approximately
0.5kb, mRNA was observable in many tissues, while
Human cDNA: NM_004590, U91746, AB007454,
a 1.5kb mRNA was observed only in the presence of
XM_008455, AF039955, AF055467, AF039954,
IL-10. Shoudai et al. (1998) also reported both 0.5kb
AB018249
and 1.5kb mRNAs, but observed expression only in
Human gene: AF088219
liver (Shoudai, et al., 1998). Similar liver-specific
expression was observed by Yang et al. (2000). The
Chromosome location identity of the cells that express HCC-4 in the liver
is unknown, however HepG2 hepatoma cells are
The human gene for HCC-4 is present at 17q11.2 reported to express HCC-4 in a constitutive manner
(Naruse et al., 1996,Younet al., 1998; Fukudaet al., (Yang et al., 2000).
1999). The mouse gene for HCC-4 appears to be a
pseudogene (Fukuda et al., 1999).
PROTEIN
Relevant linkages
Sequence
The gene for HCC-4 is separated from the gene
See Figure 1.
for HCC-1 by only 2.2kb (Fukuda et al., 1999). The
HCC-2 gene also resides 12kb from the HCC-1 gene
(Pardigol et al., 1998), thus these three chemokine Description of protein
genes are closely linked.
Mature protein (predicted): 97 amino acids (Hedrick
Regulatory sites and corresponding et al., 1998; Shoudai et al., 1998), 100 amino acids
(Youn et al., 1998).
transcription factors
The gene for human HCC-4 according to Fukuda Important homologies
et al. (1999) lacks a typical TATA box and
transcription initiates at multiple sites ((cid:135)30, (cid:135)27,
HCC-4is amember of the CC chemokine familyand
(cid:135)1). Other regulatory sites as noted by Fukuda et al.
is most homologous to HCC-1 (38% identity).
(1999) are: (cid:255)320, C/EBP(cid:12)-binding site, (cid:255)282,
Hepatocyte nuclear factor-3(cid:12)-binding site, (cid:255)117, C/
EBP(cid:12)-binding site, (cid:255)45, c/EBP binding site, (cid:255)44, Posttranslational modifications
Hepatocyte nuclear factor-3(cid:12)-binding site. The 30-
flanking region contains two AATAAA sites for
Posttranslational modification of HCC-4 has not
transcript termination that are separated by an Alu
been experimentally determined, though a single
repetitive sequence. This region also contains a single
consensussite for N-linkedglycosylationis presentin
potential mRNA instability sequence (Hedrick et al.,
the C terminus (Hedrick et al., 1998; Shoudai et al.,
1998, Shoudai et al., 1998).
1998; Youn et al., 1998).
Figure 1 Amino acid sequence for HCC-4/CCL16.
MKVSEAALSLLVLILIITSA SRSQPKVPEW VNTPSTCCLK YYEKVLPRRL VVGYRKALNC HLPAIIFVTK
RNREVCTNPNDDWVQEYIKDPNLPLLPTRNLSTVKIITAKNGQPQLLNSQ
HCC-4/CCL16 3
CELLULAR SOURCES AND microchemotaxisassays,transwellchemotaxisassays,
measurement of intracellular calcium flux, and
TISSUE EXPRESSION
cellular adhesion.
Cellular sources that produce
PATHOPHYSIOLOGICAL ROLES
Hedrick et al. (1998) have shown that monocytes
IN NORMAL HUMANS AND
express message for HCC-4. Low levels of expression
were also reported in some T cells and NK cells DISEASE STATES AND
(Hedrick et al., 1998). HepG2 hepatoma cells are DIAGNOSTIC UTILITY
reported to express HCC-4 in a constitutive manner
(Yangetal.,2000).Todate,expressionofHCC-4has
Normal levels and effects
not been studied at the protein level.
As previously mentioned, the normal physiological
Eliciting and inhibitory stimuli,
role of HCC-4 is unclear. At present some disagree-
including exogenous and ment remains regarding where HCC-4 mRNA is
expressed and nothing has been published regarding
endogenous modulators
the levels of protein present either in circulation or in
specifictissues.
The1.5kbtranscriptofHCC-4hasbeenreportedtobe
stabilized in the presence of IL-10 (Hedrick et al.,
1998).ExpressionofHCC-4inHepG2hepatomacells IN THERAPY
isupregulatedbyhypoxicexposure(Yangetal.,2000).
HCC-4 has not been used in any human studies,
RECEPTOR UTILIZATION however Giovarelli et al. (2000) have recently
reportedthatHCC-4iseffectiveinamouseantitumor
model. In this model, an aggressive and poorly
HCC-4hasbeenreportedtointeractwithtworeceptors,
immunogenic mammary adenocarcinoma line desig-
CCR1andCCR8(Howardetal.,2000).Theaffinityof
nated TSA-pc was engineered to express human
HCC-4 for these receptors has not been determined
HCC-4. Normally, TSA-pc cells grow quickly in
directly, however Howard et al. (2000) reported IC
50 either Balb/c or nu/nu mice, giving rise to lung
values of 11.8nM, 24.6nM, and 49.1nM for CCR1
metastases, and ultimately leading to death with a
basedoncompetitionwithlabeledRANTES,MIP-1(cid:11),
mean survival time of 21–25 days in the study
and MIP-1(cid:12), respectively. The affinity of HCC-4 for
reported(Giovarellietal.,2000).Interestingly,Balb/c
CCR8issomewhathigher,withanIC of7.1nMbased
50 mice injected with TSA-LEC cells generally failed to
oncompetitionwithlabeledI-309(Howardetal.,2000).
develop tumors and those which did had a mean
survival time of 67 days. The T deficient nu/nu mice
IN VITRO ACTIVITIES in contrast, still developed tumors though survival
time was increased to 34 days. Interestingly, TSA-
In vitro findings LECcellsdemonstrateddecreasedmetastaticcapacity
and were also able to induce protective immunity to
subsequent challenge with TSA-pc cells. Antibody
HCC-4 has been shown to regulate chemotaxis of
blocking experiments in this model suggest that both
lymphocytes and monocytes in vitro (Hedrick et al.,
polymorphonuclear leukocytes and CD8(cid:135) T cells are
1998;Younetal.,1998).HCC-4alsoinducescalcium
important in tumor rejection, while NK cells and
flux in human monocytes and THP-1 cells (Hedrick
CD4(cid:135) cells were not significant contributors.
et al., 1998; Youn et al., 1998). Like many other
chemokines, HCC-4 also displays myelosuppressive
activity(Younetal.,1998).
NOTE
Bioassays used
Nomiyama et al. have recently reported CCL16
interaction with CCR1, CCR2, CCR5 and CCR8.
Typical assays for chemokine activity have In Nomiyama H, Hieshima K, Nakayama T,
been employed to characterize HCC-4 including Sakaguchi T, Fujisawa R, Tanase S, Nishiura H,
4 Joseph A. Hedrick
Matsuno K, Takamori H, Tabira Y, Yamamoto T, Naruse,K.,Ueno,M.,Satoh,T.,Nomiyama,H.,Tei,H.,Takeda,
Miura R, Yoshie O. (2001). Human CC chemokine M.,Ledbetter,D.,VanCoillie,E.,Opdenakker,G.,Gunge,N.,
Sakaki,Y.,Iio,M.,andMiura,R.(1996).AYACcontigofthe
liver-expressed chemokine/CCL16 is a functional
humanCCchemokinegenesclusteredonchromosome17q11.2.
ligand for CCR1, CCR2 and CCR5, and constitu-
Genomics34,236–240.
tively expressed by hepatocytes. Int. Immunol. 13, Pardigol, A., Forssmann, U., Zucht, H.-D., Loetscher, P.,
1021–1029. Schulz-Knappe, P., Baggiolini, M., Forssmann, W.-G., and
Ma¨gert,H.-J.(1998).HCC-2,ahumanchemokine:genestruc-
ture, expression pattern, and biological activity. Proc. Natl.
Acad.Sci.USA95,6308–6313.
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