Table Of ContentMacrophage-derived
Chemokine
David Chantry and Patrick W. Gray*
ICOS Corporation, 22021 20th Avenue SE, Bothell, WA 98021, USA
*corresponding author tel: 425-485-1900, fax: 425-485-1961, e-mail: [email protected]
DOI: 10.1006/rwcy.2001.11022.
SUMMARY Alternative names
Macrophage-derived chemokine (MDC) is a member STCP-1 (stimulated T cell chemotactic protein),
oftheCCchemokinefamily.ThereceptorforMDCis ABCD-1.
CCR4, a G protein-coupled receptor expressed
primarily on the TH2 subset of T lymphocytes and
on developing T cells within the thymus. Consistent
Structure
with this expression pattern, MDC is a chemoattrac-
tantforthesecell types. MDCisalso chemotacticfor
Only the primary sequence of MDC is known. MDC
IL-2-activated NK cells, dendritic cells, and mono-
is a member of the CC family of chemokines and
cytes, although whether these effects are mediated
shares28–35%aminoacididentitywiththisgroupof
through CCR4 or another, as yet to be identified
proteins.Thissequenceconservationincludesthefour
receptor, is unclear. In vivo, MDC appears to be
characteristic cysteines and nine other highly con-
involved in the migration of developing T cells in the
served residues (Chang et al., 1997; Godiska et al.,
thymus,andofdistinctsubsetsofmatureTcellsinthe
1997).AttheC-terminusofMDCthereisastretchof
periphery. In the context of pathophysiology, MDC
basic residues which is also conserved within the
may play an important role in the migration of TH2
chemokine family and which mediates their ability to
cells during allergic inflammation, and of CLA+ T
interact with heparin.
cells to the skin in conditions such as psoriasis.
BACKGROUND Main activities and
pathophysiological roles
Discovery
MDC is chemotactic for a number of cell types,
Macrophage-derived chemokine (MDC) was origin- including thymocytes, monocytes, IL-2-activated
ally identified during the sequencing of randomly NK cells, dendritic cells, and both TH2 and CLA+
selected clones from human macrophages (Godiska T cells. In the context of pathophysiology the latter
et al., 1997; Chantry et al., 1998). A cDNA for the two activities are the most relevant. TH2 T cells are
murinehomologofMDCwassubsequentlyidentified important mediators of allergic inflammation and
using suppression subtractive hybridization to iden- MDC appears to play a role in the migration of this
tify transcripts which were upregulated following cell type in disease settings. MDC levels are elevated
stimulationofpro-preBcellswithanti-CD40andIL- in the affected tissues in murine models of asthma
4tomatureS(cid:22)-"switchedcells(Schanieletal.,1998). (Gonzalo et al., 1999) and atopic dermatitis
CytokineReference Copyright#2001AcademicPress
2 David Chantry and Patrick W. Gray
(Vestergaard et al., 1999) and in the serum and tissue etal.,1998;Bonecchietal.,1998),orbyactivationof
of humans with allergic inflammation (Galli et al., B cells (Schaniel et al., 1998) or T cells (Galli et al.,
2000).TheCLAantigenisusedtodefinethoseTcells 2000).
which selectively home to skin. It has recently been
shown that CLA+ T cells express CCR4 and will
migrate in response to MDC (Campbell et al., 1999). PROTEIN
MDCmaythereforebeinvolvedinthemigrationofT
cellstoinflamedskin.Consistentwiththis,MDCand Accession numbers
TARC (the other ligand for CCR4) have been shown
to be expressed in human psoriatic skin (Campbell
Human: U83171
et al., 1999).
Mouse: AAD50547
Sequence
GENE AND GENE REGULATION
Accession numbers See Figure 1.
Human: U83171 Description of protein
Mouse: AF1632477
Rat: AF163476
Only the primary sequence of MDC is known. MDC
is a member of the CC family of chemokines and
shares28–35%aminoacididentitywiththisgroupof
Chromosome location proteins, including four characteristic cysteines and
nine other highly conserved residues. MDC is well
conserved between species, mouse and rat MDC are
16q13
80%identicalandshare65%identitywiththehuman
gene product (Chantry et al., 1999). At the C-
terminus of MDC there is a stretch of basic residues
Regulatory sites and corresponding
which is also conserved both in MDC from different
transcription factors species and more broadly within the chemokine
family and mediates interaction with heparin
(Godiska et al., 1997).
No information is available. The genomic structure
of MDC has been determined and the intron–exon
boundaries are conserved between MDC and other Discussion of crystal structure
members of the CC chemokine family. In addition
the 30 untranslated region of the MDC cDNA is
Unknown.Structuralinformationisonlyavailableby
longer than that of other chemokines and includes
inference from other CC chemokines.
three Alu repeats (Godiska et al., 1997).
Important homologies
Cells and tissues that express
MDC is most closely related to the CC chemokine
the gene
TARC. TARC appears to be regulated in a manner
MDC is expressed at high levels in thymus, lower
levelsofexpressionareseeninlymphnode,appendix, Figure 1 Amino acid sequence for human and mouse
MDC.
small intestine and lung (Chang et al., 1997; Godiska
et al., 1997). Expression of the MDC mRNA is
upregulated during the differentiation of monocytes
to macrophages (Godiska et al., 1997) and
Langerhans cells to dendritic cells (Tang and Cyster,
1999). MDC expression can also be induced in
monocytes by treatment with IL-4 or IL-13 (Andrew
Macrophage-derived Chemokine 3
similar to MDC, it is a ligand for CCR4 and superfamily (Imai et al., 1998). It has been suggested
maps near MDC on chromosome 16q13 (Imai et al., that additional receptor(s) for MDC may be
1998). expressed on human monocytes (Struyf et al., 1999;
Proost et al., 1999) and eosinophils (Bochner et al.,
1999)andmurineTH1cells(Schanieletal.,1999).As
Posttranslational modifications
yet these receptors have not been identified at the
molecular level.
MDC has been expressed and purifed from mamma-
lian cells and does not appear to be glycosylated
(Godiska et al., 1997). MDC is processed by removal
IN VITRO ACTIVITIES
of a 24 amino acid leader sequence to generate the
mature, biologically active protein. There is evidence
In vitro findings
that MDC might undergo additional proteolytic
processing, it is a substrate in vitro for the dipeptidyl-
peptidase CD26 (Struyf et al., 1999; Proost et al., In vitro, MDC is chemotactic for a number of cell
1999),buttheinvivosignificanceofthisobservationis types including thymocytes (Cambell et al., 1999;
unclear. Chantry et al., 1999), dendritic cells, monocytes, IL-2-
activated NK cells (Godiska et al., 1997),TH2 T cells
(Bonecchietal.,1998;Sallustoetal.,1998;Imaietal.,
CELLULAR SOURCES AND 1998)andCLA+Tcells(Cambelletal.,1999).MDC
has also been reported to inhibit HIV replication
TISSUE EXPRESSION
in vitro (Pal et al., 1997; Struyf et al., 1999), although
the physiological significance of this observation is
Cellular sources that produce
still unclear.
In vitro, MDC can be made by monocytes, macro-
phages, dendritic cells, B cells, and T cells.
Regulatory molecules: Inhibitors
and enhancers
Eliciting and inhibitory stimuli,
including exogenous and Monocyte expression of MDC is inhibited by IFN(cid:13)
(Andrew et al., 1998; Bonecchi et al., 1998).
endogenous modulators
Expression of MDC can be induced by a number Bioassays used
of different stimuli. In monocytes MDC expression
isinducedbyIL-4,IL-13,andGM-CSF(Andrewetal.,
MDC biological activity is assayed by calcium flux
1998;Bonecchietal.,1998).ActivationofTcellswith
or chemotaxis using either primary cells or more
antibodies to CD3 and CD28, or by using calcium
commonly stable transfectants expressing CCR4
ionophore and phorbol ester, elicit MDC production
(Imai et al., 1998).
(Gallietal.,2000),whileBcellsanddendriticcellscan
be stimulated to produce MDC by activation with
CD40L (Schaniel et al., 1998). MDC is also made
constitutively by differentiated human macrophages IN VIVO BIOLOGICAL
(Godiska et al., 1997), and dendritic cells (Godiska
ACTIVITIES OF LIGANDS IN
et al., 1997; Tang and Cyster, 1999).
ANIMAL MODELS
The induction of MDC expression in human
monocytes by IL-4 or IL-13 is inhibited by IFN(cid:13)
(Andrew et al., 1998; Bonecchi et al., 1998). Normal physiological roles
In normal tissues, MDC mRNA is expressed at
RECEPTOR UTILIZATION
highest levels in thymus (Godiska et al., 1997).
Immunocytochemistry has been used to localize
MDC is a ligand for the receptor CCR4 which is MDC expression within the thymus to the medulla
a member of the G protein-coupled receptor (Chantryetal.,1999)andMDChasbeenshowntobe
4 David Chantry and Patrick W. Gray
chemotactic for thymocytes (Chantry et al., 1999; PATHOPHYSIOLOGICAL ROLES
Campbell et al., 1999). These findings suggest that
IN NORMAL HUMANS AND
MDC may play a role in the migration of developing
DISEASE STATES AND
T cells from the cortex to the medulla. There is also
evidencethatMDCmaybeinvolvedinthemigration DIAGNOSTIC UTILITY
of T cells during an immune response. Following
antigenic challenge in the skin Langerhans cells take Normal levels and effects
upantigen,migratetodraininglymphnodes,undergo
a program of differentiation to dendritic cells and
MDCispresentinserumofnormalindividuals(200–
present antigen to T cells. MDC is not expressed
1000pg/mL)(Gallietal.,2000),butthephysiological
by na(cid:127)(cid:16)ve Langerhans cells, but as differentiation to
significanceofthisisunknown.Immunocytochemistry
the dendritic cells takes place, MDC expression is
has also revealed expression of MDC protein in the
dramatically upregulated (Tang and Cyster, 1999).
thymus, where it may play a role in the migration of
These findings suggest that MDC may be involved in
developing T cells (Chantry et al., 1999).
the colocalization of T cells and dendritic cells within
the lymph node during the generation of an immune
response (Kanazawa et al., 1999; Tang and Cyster,
Role in experiments of nature and
1999).
disease states
Species differences
MDC levels are significantly elevated in the serum of
patients with diseases characterized by the activation
MDC is well conserved between species; mouse and of TH2 T cells and this is associated with local
human MDC are 65% identical at the amino acid expressionofMDCatdiseasesites(Gallietal.,2000).
level (Chantry et al., 1999), and murine MDC will MDCexpressionhasalsobeenfoundtobeelevatedin
signal through human CCR4. In addition, the in vivo a murine model of asthma (Gonzalo et al., 1999) and
expression pattern of MDC appears to be similar in in a spontaneous mouse model of atopic dermatitis
humans and rodents (Chang et al., 1997; Godiska (Vestergaard et al., 1999).
et al., 1997; Chantry et al., 1999).
IN THERAPY
Interactions with cytokine network
Effects of therapy: Cytokine,
The induction of MDC expression in human
antibody to cytokine inhibitors, etc.
monocytes by IL-4 or IL-13 is inhibited by IFN(cid:13)
(Bonecchi et al., 1998).
Neutralizing antibodies to MDC have been shown to
block airway hyperreactivity in a murine model of
Endogenous inhibitors and
asthma (Gonzalo et al., 1999).
enhancers
References
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