Table Of ContentSDF-1
Charles R. Mackay*
The Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst (Sydney),
New South Wales, 2010, Australia
*corresponding author tel: 61-2-92958405, fax: 61-2-92958404, e-mail: [email protected]
DOI: 10.1006/rwcy.2000.10010.
SUMMARY proliferation which was distinct from IL-7 and stem
cell factor (Nagasawa et al., 1994). A cDNA clone
encoding this growth-stimulating factor was isolated
SDF-1 is a CXC chemokine that has several
by expression cloning. In the third study, a partial
distinguishing features. It widely expressed and has
cDNA sequence, termed TPAR1 (TPA repressed
a broad range of actions, affecting T cell chemotaxis,
gene 1), was isolated from a cDNA library con-
B cell chemotaxis, B cell development, CD34(cid:135) stem
structed from mouse embryo fibroblasts treated with
cellmigration,andneuraldevelopment,aswellasthe
TPA. Full-length clones were later isolated (Jiang
development and vascularization of various other
et al., 1994).
tissues. SDF-1 appears to be particularly important
Two alternatively spliced SDF-1 mRNAs encode
for basal trafficking of cells, for instance naı¨ve T cell
SDF-1(cid:11) (68 residues) and SDF-1(cid:12) (72 residues). The
traffic through lymph nodes, rather than the
four additional residues of SDF-1(cid:12) are located at the
trafficking of effector leukocytes to inflammatory
C-terminus (Shirozu et al., 1995). A form that had
lesions. SDF-1 is highly conserved between mouse
beenprocessedattheC-terminalendtogeneratea67
and human, and binds to the chemokine receptor
residue protein was purified from stromal cells (Bleul
CXCR4. SDF-1 is able to inhibit T-tropic HIV-1
etal.,1996a).AnunusualfeatureofSDF-1isthatthe
entry into CXCR4-bearing cell lines, and SDF-1
human and mouse molecules are virtually identical;
expression may have an important bearing on AIDS
there is a single conservative change: Val to Ile at
pathogenesis, since a polymorphism in the human
position 18 (Shirozu et al., 1995). This conservation
SDF-1 gene affects the onset of AIDS.
has led to speculation that SDF-1 has fundamental
functions, and may be a primordial chemokine.
BACKGROUND
Discovery Alternative names
SDF-1 was discovered by three groups independently SDF-1(cid:11) (and its alternative form SDF-1(cid:12)) were
(Tashiro et al., 1993; Jiang et al., 1994; Nagasawa described as such in 1993 (Tashiro et al., 1993),
etal.,1994).Inonestudy,amethodwasdevelopedto although this molecule was also reported as ‘pre-B-
clone cDNAs that carry N-terminal signal sequences cell growth-stimulating factor’ (PBSF) (Nagasawa
(signal sequence Trap) (Tashiro et al., 1993). An etal.,1994),aswellas‘TPAR-1’(TPArepressedgene1)
expression cDNA library was constructed from a (Jiang et al., 1994). SDF-1 is now the recognized and
bone marrow stromal cell line, and two cDNAs that universally used name.
encoded chemokines, stromal cell-derived factor-1(cid:11)
(SDF-1a) and SDF-1b were cloned (Tashiro et al.,
Structure
1993). In another study, SDF-1 was found by virtue
of its ability to stimulate early B cell progenitors
(Nagasawaetal.,1994).Astromalcellline,PA6,was SDF-1 is a member of the (CXC) chemokines,
found to produce a soluble mediator for B cell althoughitdoesnotcontaintheELRmotiftypicalof
1120 Charles R. Mackay
the IL-8-like chemokines. The amino acid sequence lymphocytes,forinstancethroughlymphnodes,rather
contains four cysteine residues conserved by most of than to inflammatory lesions. SDF-1 is one of four
theCXCchemokines.TheN-terminusofSDF-1may chemokines that is able to induce firm adhesion and
be particularly important for activity, since peptides arrest of rolling T cells under flow conditions
corresponding to the N-terminal 9 residues of SDF-1 (Campbell et al., 1998). SDF-1, as well as 6C-kine
were able to induce intracellular calcium and chemo- and MIP-3(cid:12), induced adhesion of most circulating
taxis in T lymphocytes, and bind to CXCR4 lymphocytes to ICAM-1 under flow (Campbell et al.,
(Loetscher et al., 1998). The crystal structure of 1998).
SDF-1 is discussed below.
CD34 Cell Migration
Main activities and Hematopoietic progenitor cells were shown to mig-
rate in vitro and in vivo towards a gradient of SDF-1
pathophysiological roles
producedbystromalcells.CD34(cid:135)migratingtoSDF-
1 included cells with a more primitive (CD34(cid:135)/
Much of this discussion is also relevant for CXCR4 CD38(cid:255) or CD34(cid:135)/DR(cid:255)) phenotype as well as
function and pathological role, since SDF-1 and CD34(cid:135) cells phenotypically committed to the ery-
CXCR4 are a monogamous receptor ligand pair. throid, lymphoid, and myeloid lineages (Aiuti et al.,
The receptor for SDF-1, CXCR4, is widely 1997).
expressedonleukocytes,maturedendriticcells,endo-
thelial cells, brain cells, and megakaryocytes, hence Brain Cells
theactivitiesofSDF-1arenumerousandvaried.This
A role for SDF-1, and its receptor CXCR4, in
chemokine,morethananyotherchemokineidentified
neuronal development is inferred from studies with
thus far, has the widest range of biological functions,
CXCR4-deficient mice (Zou et al., 1998), as well as
especially outside of the immune system. The most
immunohistochemical localization of SDF-1 and its
significant functional effects of SDF-1 are outlined
receptor to various cell types in the brain. One study
below.
showedthatSDF-1coulddirectlyinduceapoptosisin
a neuronal cell line (Hesselgesser et al., 1998).
B Cell Development and Migration
SDF-1 was originally identified through its ability to HIV Infection
support the proliferation of a stromal cell-dependent
CXCR4 serves as a coreceptor for T-tropic strains of
pre-B cell clone and augment the growth of bone
HIV-1, and SDF-1 is able to block T-tropic HIV-1
marrow B cell progenitors in the presence of IL-7
entry into CXCR4-bearing cells (Bleul et al., 1996b;
(Nagasawaetal.,1994).Thisresult,togetherwiththe
Oberlin et al., 1996). The significance of CXCR4 for
analysis of SDF-1- and CXCR4-deficient mice show
HIV entry and AIDS pathogenesis is discussed more
that SDF-1 is critical for B cell development.
fully in the chapter on CXCR4 (Moore et al., 1997).
SDF-1isalsoaBcellchemoattractant,andCXCR4
SDF-1 expression may have an important bearing on
isexpressedonBcellsatvariousstagesofmaturation
AIDS pathogenesis. A polymorphism was identified
oreffectorfunction(D’Apuzzoetal.,1997;Bleuletal.,
in an evolutionarily conserved region of the 30 UTR
1998).Inhumans,SDF-1attractsnaı¨veandmemory,
of the human SDF-1 gene. In the homozygous state,
butnotgerminalcenterBcells(Bleuletal.,1998).The
this polymorphism delayed the onset of AIDS, and
receptor for SDF-1, CXCR4, was found on respon-
this protective effect was twice as strong as the
sive (as well as some unresponsive) B cell subsets.
dominant genetic restriction of AIDS conferred by
mRNA for SDF-1 was detected by in situ hybridiza-
CCR5 and CCR2 chemokine receptor variants
tioninalayerofcellssurroundingthegerminalcenter,
(Winkler et al., 1998).
suggesting that SDF-1 is important for the position-
ing of B cells within secondary lymphoid tissue.
GENE AND GENE REGULATION
T Cell Chemotaxis
Accession numbers
SDF-1 is one of the most efficacious T cell chemo-
attractants (Bleul et al., 1996b).This probably relates
to the wide expression of CXCR4 on many T cells, Human: 1352728, 730278, 3914966, U16752
particularly naı¨ve T cells (Bleul et al., 1997). SDF-1 Mouse: D21072, D43804, D43805, 539916, L12029,
may be more important for basal trafficking of L12030, S74318
SDF-1 1121
Chromosome location Sequence
ThehumanSDF-1genemapstochromosome10qby See Figure 1.
fluorescence in situ hybridization (Shirozu et al.,
1995), which is unusual given that genes encoding Discussion of crystal structure
other members of the chemokine family are localized
on chromosome 4q or 17q. The three-dimensional structure of SDF-1 was deter-
mined by NMR spectroscopy (Crump et al., 1997).
SDF-1wasfoundtobeamonomerwithadisordered
Regulatory sites and corresponding
N-terminal region (residues 1–8), and differed from
transcription factors other chemokines in the packing of the hydrophobic
core and surface charge distribution. This study
showed that residues 12–17 of the loop region
A GC-rich sequence in the 50-flanking region of the
(RFFESH motif) formed a receptor-binding site,
SDF-1 gene, similar to other ‘housekeeping’ genes,
which was proposed as an important initial docking
may relate to the ubiquitous expression of SDF-1.
site for SDF-1 with its receptor (Crump et al., 1997).
Other regulatory elements are unknown.
A crystal structure of a variant SDF-1(cid:11) ([N33A]-
SDF-1(cid:11), prepared by chemical synthesis) has been
refined to 2.2A˚ resolution (Dealwis et al., 1998).
Cells and tissues that express
SDF-1(cid:11) shows the typical chemokine (cid:12)-(cid:12)-(cid:12)-(cid:11)
the gene topology, although the packing of the (cid:11) helix against
the (cid:12) sheet was found to be strikingly different.
Structural analysis also revealed a positively
An unusual feature of SDF-1 is that it is expressed
charged surface that may be important for binding
constitutively by many cell types (Shirozu et al.,
to the negatively charged extracellular loops of
1995), in contrast to many other chemokines which
CXCR4 (Dealwis et al., 1998).
are induced by inflammatory cytokines. This prob-
ablyrelatestothebroadfunctionalactivityofSDF-1,
Important homologies
in particular its role in nonimmune cell migration,
positioning or survival. The exact function of SDF-1
is still poorly understood, and so the significance of SDF-1 is a member of the chemokine family,
its wide expression is currently speculative. By simple althoughitisdistinctiveinthatthemouseandhuman
northernblot,mRNAforSDF-1isexpressedinbrain, proteins are highly conserved (99%). Although SDF-
heart, liver, bone marrow, kidney, spleen, stomach, 1 is a CXC chemokine, it is relatively distinct from
and gastrointestinal tract. Stromal cells express high otherbranchesofthisfamily,suchastheIL-8family,
levelsofSDF-1,particularlythosethatsupportBcell and the IP-10, MIG, I-TAC family.
lymphopoiesis.
CELLULAR SOURCES AND
TISSUE EXPRESSION
PROTEIN
Cellular sources that produce
Accession numbers
SDF-1 is produced by a broad range of cell types, in
SwissProt: P40224, P48061 particular by bone marrow stromal cells, as well as
Figure 1 Amino acid sequence of SDF-1(cid:11) and SDF-1(cid:12); the
signal peptide is underlined.
SDF-1a
MNAKVVVVLV LVLTALCLSD G KPVSLSYRC PCRFFESHVA RANVKHLKIL
NTPNCALQIV ARLKNNNRQV CIDPKLKWIQ EYLEKALNK
SDF-1b
MNAKVVVVLV LVLTALCLSD G KPVSLSYRC PCRFFESHVA RANVKHLKIL
NTPNCALQIV ARLKNNNRQV CIDPKLKWIQ EYLEKALNKR FKM
1122 Charles R. Mackay
numerous others (Shirozu et al., 1995) (see above), cell progenitors in mutant embryos were severely
althoughtheseanalyseshavebeenmostlyattheRNA reduced in fetal liver and bone marrow, and myeloid
level. There have been few reports on SDF-1 protein progenitors were reduced in the bone marrow (but
localization. not in the fetal liver). In addition, the mutants had a
cardiacventricularseptaldefect,whichmaybeoneof
the reasons for lethality (Nagasawa et al., 1996). In
another study, SDF-1- (and CXCR4)-deficient mice
RECEPTOR UTILIZATION
werefoundtohaveseverelyreducedBlymphopoiesis,
reduced or absent myelopoiesis in fetal liver or bone
SDF-1 binds the chemokine receptor CXCR4 marrow, but normal T lymphopoiesis. Moreover, the
(Bleul et al., 1996b; Oberlin et al., 1996). SDF-1 and cerebellum was found to develop abnormally in this
CXCR4 are monogamous partners. study (Ma et al., 1998). In another study by the
Japanese group, a role for SDF-1 (and its receptor
CXCR4) was implicated in the vascularization of
IN VITRO ACTIVITIES various tissues, particularly the gastrointestinal tract
(Tachibana et al., 1998). In another study using
CXCR4-deficient mice, hematopoietic and cardiac
In vitro findings
defectsidenticaltothoseofSDF-1-deficientmicewere
noted, as well as altered fetal cerebellar development,
SDF-1 supports the proliferation of a stromal cell- indicating a role for CXCR4 (and its ligand) in
dependent pre-B cell clone and augments the growth neuronal cell migration and patterning in the central
of bone marrow B cell progenitors in the presence of nervous system (Zou et al., 1998).
IL-7 (Nagasawa et al., 1994). SDF-1 is also a B cell
chemoattractant, attracting naı¨ve and memory, but
notgerminalcenterBcells (Bleulet al.,1998).SDF-1
PATHOPHYSIOLOGICAL ROLES
is one of the most efficacious T cell chemoattractants
(Bleul et al., 1996a). SDF-1 is able to induce firm IN NORMAL HUMANS AND
adhesion and arrest of rolling T cells under flow
DISEASE STATES AND
conditions (Campbell et al., 1998). CD34(cid:135) hemato-
DIAGNOSTIC UTILITY
poieticprogenitorcellswereshowntomigrateinvitro
andin vivotowardsagradientofSDF-1 producedby
stromal cells (Aiuti et al., 1997). SDF-1 blocks the Role in experiments of nature and
infection in vitro of T cells with T-tropic strains of
disease states
HIV-1 (Bleul et al., 1996b; Oberlin et al., 1996).
Disease association has not been defined, although
high levels of SDF-1 may have a bearing on the
Bioassays used
spread of T-tropic HIV-1.
The most common bioassay used for SDF-1 is a
chemotaxis assay (Qin et al., 1996), although SDF-1
IN THERAPY
also elicits other responses such as calcium flux.
Effects of therapy: Cytokine,
IN VIVO BIOLOGICAL antibody to cytokine inhibitors, etc.
ACTIVITIES OF LIGANDS IN
The therapeutic utility of SDF-1 revolves more
ANIMAL MODELS
around its antagonism, rather than its stimulation
of various cell types. For instance, small molecule
Knockout mouse phenotypes
antagonists have been developed that block SDF-1
binding to its receptor, CXCR4 (Donzella et al.,
In the two studies that have been reported, SDF-1 is 1998). The utility of such drugs would be for inhi-
essential for embryonic development, since mice bition of HIV infection. Such drugs may find wider
lacking SDF-1 died perinatally (Nagasawa et al., applications, although at present such applications
1996;Maetal.,1998).Inthefirststudy,numbersofB are not obvious.
SDF-1 1123
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