НСС-1

4 Pages·2000·0.079 MB·English

by  Salcedo T.

HCC-1
Theodora W. Salcedo*
Human Genome Sciences, Inc., 9410 Key West Avenue, Rockville, MA 20850, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.11014.
SUMMARY Alternative names
HemofiltrateCCchemokine(HCC-1/NCC-2/CK(cid:12)-1/ HCC-1wasfirstidentifiedashemofiltrateCCchemo-
M-CIF) is a (cid:12) chemokine family member that shares kine (Schulz-Knappe et al., 1996). This chemokine
highest structural similarity with macrophage inflam- was also discovered independently by other groups
matory protein (MIP)-1(cid:11). Cross-desensitization and was named new CC chemokine 2 (NCC-2) and
experiments suggest that HCC-1 and MIP-1(cid:11) share CK(cid:12)-1/M-CIF. The designation HCC-3 corresponds
a common receptor. CCR1 was identified as a func- to an uncharacterized splice variant of HCC-1.
tional HCC-1 receptor upon analysis of transfectants
expressing various cloned chemokine receptors.
Functionally, HCC-1 displays calcium mobilization Structure
and chemotactic activity toward monocytes, but with
100-fold reduced potency compared with MIP-1(cid:11).
HCC-1isamemberoftheCCor(cid:12)chemokinefamily.
HCC-1 fails to activate T lymphocytes, neutrophils,
The complete sequence encodes for a 93 amino acid
and eosinophils, but displays activity on myeloid
chemokine with a putative N-terminal 19 amino acid
progenitors. Unlike most CC chemokines, it is con-
leader sequence followed by a mature protein of 74
stitutively expressed in many tissues without activa-
amino acids. Signal sequence cleavage is predicted to
tion and is present in nanomolar concentrations in
occur at residue 19, with the N-terminal amino acid
normal human plasma.
beingmethionine(HCC-1(20–93)).Thisistheformof
the protein isolated from renal patient hemofiltrate
BACKGROUND (Schulz-Knappe et al., 1996). Two additional N-
terminally truncated variants of HCC-1 have been
generatedandactivitycomparedwithHCC-1(20–93).
Discovery
The shorter forms (HCC-1(23–93) and HCC-1(25–
93))weresignificantlymorepotentinchemotaxisand
HCC-1 was initially described as a hemofiltrate CC
cAMP assays compared toHCC-1(20–93). Fourcon-
chemokine after the protein was purified from hemo-
served cysteines typical of the CC chemokine family
filtrate collected from patients with chronic renal
are present in HCC-1 at amino acid positions 35, 36,
failure and the HCC-1 cDNA was isolated from a
59, and 75. The observed molecular mass for HCC-1
human bone marrow cDNA library (Schulz-Knappe
purified from hemofiltrate is 8673.
et al., 1996). In another study, a novel expressed
sequencetag(EST)forthischemokinewasmappedto
the CC chemokine cluster on chromosome 17, and Main activities and
namedNCC-2fornewCCchemokine2(Naruseetal.,
pathophysiological roles
1996). A third group identified a cDNA encoding
CK(cid:12)-1intheHGS/TIGRdatabaseaspartofalarge-
scale sequencing effort and subsequently named the HCC-1 displays functional activity towards mono-
chemokine monocyte colony inhibitory factor (M- cytes, but not T lymphocytes, eosinophils or neutro-
CIF)toreflectfunctionalactivity(Kreideretal.,1996). phils. On monocytes, it induces a rise of intracellular
1266 Theodora W. Salcedo
Ca2(cid:135) and a slight release of N-acetyl-(cid:12)-D-glucosami- localizedinaclusteronchromosome17thatcontains
nidase (Schulz-Knappe et al., 1996). The amount of several CC chemokines, including MCP-3, MCP-1,
HCC-1 needed for these responses is 100 and NCC-1, I-309, and RANTES (Naruse et al., 1996).
1000nM, respectively. While in one report, HCC-1
failed to stimulate monocyte chemotaxis (Schulz-
Knappe et al., 1996), a second study demonstrated
Relevant linkages
significant chemotactic activity for monocytes (Tsou
et al., 1998). In line with the potency of HCC-1 in
By analyzing the 50 flanking region of the gene
calcium flux and degranulation assays, the optimal
encodingHCC-1,itwasfoundthatHCC-1isarrayed
concentration of HCC-1 needed to induce monocyte
in tandem with the gene for HCC-2 (Pardigol et al.,
chemotaxis is 100nM relative to 1nM for MIP-1(cid:11).
1998).Thesetwogenesareseparatedby12kbandlie
Onmonocytes,cross-desensitizationexperimentssug-
in a head-to-tail orientation. HCC-2 displays a four
gest that HCC-1 acts through a shared receptor with
exons and three intron structure, while HCC-1, like
MIP-1(cid:11). Pretreatment of monocytes with MIP-1(cid:11) or
other CC chemokines, has a three exonz–two intron
RANTES, but not MIP-1(cid:12), inhibited a subsequent
structure. The HCC-2/HCC-1 gene complex encodes
intracellular calcium response to HCC-1 (Schulz-
for the expression of both bicistronic and mono-
Knappe et al., 1996; Tsou et al., 1998). In the
cistronic transcripts (Pardigol et al., 1998). While
reciprocal experiment, HCC-1 reduced the calcium-
HCC-1 monocistronic mRNA is expressed highly in
mobilizingactivityofMIP-1(cid:11)andRANTES,butnot
all tissues except brain, placenta, and leukocytes,
MIP-1(cid:12) (Schulz-Knappe et al., 1996; Tsou et al.,
HCC-2monocistronicandHCC-1/HCC-2bicistronic
1998).Inexperiments withHEK-293cells transfected
transcriptsweremorerestrictedinexpressionincolon
with CCR1, HCC-1 competed for MIP-1(cid:11) binding,
and liver (Pardigol et al., 1998).
mobilized calcium, and induced chemotaxis, but with
100-fold lower affinity/potency compared with MIP-
1(cid:11).SpecificityofHCC-1forCCR1wasdemonstrated
using HEK-293 cells transfected with other known Regulatory sites and corresponding
chemokine receptors (CCR2, CCR3, CCR4, CCR5,
transcription factors
CCR6, CCR7, CCR8, or CXCR1) which fail to
mobilize calcium or induce chemotaxis in response to
The promoter for HCC-1 was identified by primer
HCC-1 (Tsou et al., 1998).
extensionandRT-PCR.Severalputativebindingsites
HCC-1 also displays activity toward bone marrow
were identified for transcriptional factors, including
cells.ItenhancestheproliferationofCD34(cid:135)cellsand
Myc-Max, E47, and AP-2 (Pardigol et al., 1998).
very early progenitor/stem cells of CD34(cid:135)/CD38(cid:255)
phenotype (Schulz-Knappe et al., 1996). On both
mouse and human bone marrow progenitor cells,
HCC-1 inhibits M-CSF-mediated colony formation Cells and tissues that express
(Kreider et al., 1996).
the gene
BynorthernanalysismonocistronicmRNAforHCC-
GENE AND GENE REGULATION
1 is detected in many tissues (spleen, colon, small
intestine, liver, skeletal, and heart muscle). Little or
Accession numbers
no expression is detected in kidney, brain, placenta,
leukocytes, monocyte cell lines (U937, THP1), and
Human gene: AC004675, AF088219, Z49269 HL-60 or Jurkat cells (Schulz-Knappe et al., 1996;
Human mRNA: Z49270, Z70292, Z70293 Pardigol et al., 1998).
HCC-3, uncharacterized splice variant of HCC-1:
Z70293
PROTEIN
Chromosome location
Accession numbers
The human HCC-1 gene maps to chromosome 17q
11.2 (Naruse et al., 1996; Pardigol et al., 1998). By SwissProt:
YAC contig-based mapping, the HCC-1 gene was Human: Q16627
HCC-1 1267
Figure1 AminoacidsequenceforHCC-1.Signalpeptide that CCR1 is a functional receptor for HCC-1
is underlined. (Pardigoletal.,1998).HCC-1competeswithMIP-1(cid:11)
binding to CCR1-transfected cells, but binds with
MKISVAAIPF FLLITIALGT KTESSSRGPY HPSECCFTYT TYKIPRQRIM reduced affinity compared to MIP-1(cid:11) (IC =93nM
50
DYYETNSQCS KPGIVFITKR GHSVCTNPSD KWVQDYIKDM KEN versus 1.3nM for MIP-1(cid:11)) (Pardigol et al., 1998).
Sequence
IN VITRO ACTIVITIES
See Figure 1. Regulatory molecules: Inhibitors
and enhancers
Important homologies
Although HCC-1 is constitutively expressed by many
HCC-1isamemberoftheCCor(cid:12)chemokinefamily. tissues and exists in high concentration in normal
It displays highest structural homology to MIP-1(cid:11) serum, little is known about the regulation of this
(46% amino acid sequence identity), MPIF1 (44% gene.
identity), HCC-4 (42% identity), and HCC-2 (36%
identity).
Bioassays used
Posttranslational modifications
Several bioassayshavebeen usedfor studyofHCC-1
functional activity. These include calcium mobiliza-
Based on amino acid and nucleotide sequence tion, chemotaxis, enzyme release, and adenyl cyclase
analysis, no apparent N- or O-linked glycosylation activity.
sites are present in HCC-1.
PATHOPHYSIOLOGICAL ROLES
CELLULAR SOURCES AND
IN NORMAL HUMANS AND
TISSUE EXPRESSION
DISEASE STATES AND
Cellular sources that produce DIAGNOSTIC UTILITY
Normal levels and effects
Expression of HCC-1 has been detected in many
tissues at the level of mRNA (spleen, colon, small
intestine, liver, skeletal, and heart muscle). Little or The levels of HCC-1 in human plasma range from 1
no expression is detected in kidney, brain, placenta, to 10nM in healthy subjects and 2–80nM in patients
and leukocytes (Schulz-Knappe et al., 1996; Pardigol with chronic renal failure (Schulz-Knappe et al.,
et al., 1998). There is little information regarding the 1996). This high expression level of HCC-1 is unique
regulation of the protein at the cellular level, except within the human chemokine family and the
thathighconcentrationsofHCC-1arefoundinnormal significance of this observation is unknown.
plasma. Using western blotting of plasma samples,
HCC-1 migrates as a single band of approximately
8kDa,withnodegradationproducts(Schulz-Knappe IN THERAPY
et al., 1996).
Preclinical – How does it affect
RECEPTOR UTILIZATION disease models in animals?
Basedoncalciumcross-desensitizationstudies,HCC- The sepsis syndrome is a life-threatening systemic
1 shares a functional receptor with MIP-1(cid:11) (Schulz- inflammatoryresponsetomicrobialinfectionandmay
Knappeetal.,1996;Pardigoletal.,1998).Experiments be complicated by the development of shock and
using a panel of cloned chemokine receptors (CCR1, multiple organ failure. Bacterial products such as
CCR2, CCR3, CCR4, CCR5, or CXCR1) revealed endotoxin are believed to contribute to sepsis by
1268 Theodora W. Salcedo
causing the release of inflammatory cytokines from Naruse, K., Ueno, M., Satoh, T., Nomiyama, H., Tei, H.,
activated macrophages. Prophylactic administration Takeda,M.,Ledbetter,D.H.,VanCoillie,E.,Opdenakker,G.,
Gunge,N.,Sakaki,Y.,Iio,M.,andMiura,R.(1996).AYAC
of recombinant human HCC-1/M-CIF by the intra-
contigofthehumanCCchemokinegenesclusteredonchromo-
peritoneal route substantially reduced lethality in
some17q11.2.Genomics34,236–240.
endotoxin-challengedmice(Zhangetal., 1996,1997). Pardigol,A.,Forssmann,U.,Zucht,H.D.,Loetscher,P.,Schulz-
In the HCC-1/M-CIF-treated groups, serum levels of Knappe,P.,Baggiolini,M.,Forssmann,W.G., Ma¨gert,H.-J.
IL-10 were significantly increased; however levels of (1998).HCC-2,ahumanchemokine:genestructure,expression
pattern,andbiologicalactivity. Proc.NatlAcad.Sci.USA95,
the proinflammatory cytokines were not markedly
6308–6313.
altered. Downregulation of proinflammatory cyto-
Schulz-Knappe,P.,Ma¨gert,H.-J.,Dewald,B.,Meyer,M.,Cetin,Y.,
kine production did not contribute to the protective Kubbies, M., Tomeczkowski, J., Kirchhoff, K., Raida, M.,
effects of HCC-1/M-CIF against endotoxemia. Adermann, K., Kist, A., Reinecke, M., Sillard, R.,
Interestingly, although HCC-1/M-CIF and the Pardigol, A., Uguccioni, M., Baggiolini, M., and
Forssmann, W.-G. (1996). HCC-1, a novel chemokine from
chemokine MCP-1 differ markedly in chemoattrac-
humanplasma.J.Exp.Med.183,295–299.
tant and other biological properties, MCP-1 was
Standiford,T.J.,Strieter,R.M.,Lukacs,N.W.,andKunkel,S.L.
reported to elicit protective effects in murine endo- (1995a).NeutralizationofIL-10increaseslethalityinendotox-
toxemia that were similar to those of HCC-1/M-CIF emia.Cooperativeeffectsofmacrophageinflammatoryprotein-
(Zisman et al., 1997).MCP-1 protectedagainst letha- 2andtumornecrosisfactor.J.Immunol.155,2222–2229.
Standiford,T.J.,Kunkel,S.L.,Lukacs,N.W.,Greenberger,M.F.,
lity when administered prophylactically to mice and
Danforth, J. M., Kunkel, R. G., and Strieter, R. M. (1995b).
caused similar changes in the pattern of circulating
Macrophageinflammatoryprotein-1(cid:11)mediateslungleukocyte
cytokine levels (increased IL-10). As with HCC-1/M- recruitment, lung capillary leak, and early mortality in murine
CIF,however,noclearexplanationfortheprotection endotoxemia.J.Immunol.155,1515–1524.
couldbedetermined.OtherchemokinessuchasMIP- Tsou,C.-L.,Gladue,R.P.,Carroll,L.A.,Paradis,T.,Boyd,J.G.,
Nelson,R.T.,Neote,K.,andCharo,I.F.(1998).Identification
2(Standifordetal.,1995a),MIP-1(cid:11)(Standifordetal.,
ofC-Cchemokinereceptor1(CCR1)asthemonocytehemofil-
1995b), and RANTES (VanOtteren et al., 1995),
trateC-Cchemokine(HCC)-1receptor.J.Exp.Med.188,603–
which have robust proinflammatory properties, were 608.
reported to be expressed during murine, baboon, and VanOtteren,G.M.,Strieter,R.M.,Kunkel,S.L.,PaineR.,III,
human endotoxemia. Results using various neutrali- Danforth,J.M.,Burdick,M.D.,andStandiford,T.J.(1995).
CompartmentalizedexpressionofRANTESinamurinemodel
zation strategies suggest that these chemokines may
ofendotoxemia.J.Immunol.154,1900–1908.
mediatetheinfluxofinflammatorycellsintothelungs
Zhang,J.,Kreider,B.L.,Li,H.,Su,J.,Zhang,J.L.,Gentz,R.,
and other target organs after endotoxin challenge. Garotta, G., and Antonaccio, M. (1996). Prevention of a
Thus, HCC-1/M-CIF, similar to other members of (cid:12)-chemokine on LPS-induced septic shock. Eur. Cytokine
the chemokine family, appears to contribute to the Netw.7,507(abstract207).
Zhang, J., Sturm, B., Kao, V., and Antonaccio, M. (1997).
regulation of both pro- and anti-inflammatory
Selective modulation of TNF-(cid:11) and IL-10 by M-CIF
responses during experimental endotoxemia.
(HCC-1) correlates with its protective effect on LPS-mediated
lethalsepsisinSCIDmice.J.Leukoc.Biol.34(abstract343).
Zisman, D. A., Kunkel, S. L., Strieter, R. M., Tsai, W. C.,
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