IL-8

8 Pages·0.115 MB·English

by  Iizasa H., Matsushima K.

IL-8
Hisashi Iizasa1 and Kouji Matsushima2,*
1Department of Pharmaceutics, Kyoritsu College of Pharmacy, Shibakoen 1-5-30,
Minato-ku, Tokyo 105-8512, Japan
2Department of Molecular Preventive Medicine, School of Medicine, University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.10003.
SUMMARY Alternative names
Interleukin8(IL-8),aproinflammatorychemokine,is IL-8 has also been named monocyte-derived neu-
produced by various types of cells upon stimulation trophil chemotactic factor (MDNCF) (Matsushima
with inflammatory stimuli and exerts a variety of etal.,1988),neutrophil-activatingfactor(NAF)(Walz
functions on leukocytes, particularly, neutrophils et al., 1987), neutrophil-activating protein 1 (NAP-1)
in vitro. Recent studies show that inhibition of IL-8 (Schroder et al., 1987), granulocyte chemotactic
functionsbyeitheradministrationofspecificantibody peptide (GCP) (Van Damme et al., 1988), leukocyte
or disruption of the gene encoding the IL-8 receptor adhesion inhibitor (LAI) (Gimbrone et al., 1989).
dramaticallyreducedneutrophilsinfiltrationintoacute
inflamed tissues. IL-8 plays an pivotal role in acute
inflammationbyrecruitingandactivatingneutrophils.
Structure
Four types of differentially processed forms of IL-8,
BACKGROUND
consisting of 69, 72, 77, and 79 amino acids, are
known. Among these variants, the 72 amino acid
Discovery
form is predominant and has greatest activity on
neutrophils. In addition, IL-8 is a dimer at high con-
In the early 1980s, Matsushima and coworkers puri- centrations. The dimer interface is formed by three
fied IL-1(cid:11) from LPS-stimulated human monocyte antiparallel (cid:12) strands from each monomer and the
culture supernatants. Partially purified IL-1(cid:11) or (cid:11) helices are formed in the C-terminal region.
IL-1(cid:12) hadbeenclaimedtobechemotacticforneutro-
phils at that time, although highly purified prepara-
tions of either form were not. This result indicated Main activities and
that contaminants in partially purified IL-1(cid:11) had
pathophysiological roles
neutrophil chemotactic activity. The factor with this
activity was then purified by Yoshimura et al. (1987)
and molecularly cloned from the cDNA library of IL-8 has a chemotactic activity for neutrophils
LPS-stimulatedhumanmonocytes(Matsushimaetal., and also activates neutrophil functions. It also
1988). It was initially named monocyte-derived induces angiogenesis and inhibits the proliferation
neutrophil chemotactic factor (MDNCF). MDNCF of myeloid progenitor cells. High levels of IL-8 have
was found to have additional target cells including T been detected in biofluids of various acute inflam-
lymphocytes (Larsen et al., 1989). Therefore, matory diseases. IL-8 is an essential factor
MDNCF was renamed as interleukin 8 (IL-8) for neutrophil infiltration in most inflammatory
(Balkwill and Burke, 1989). reactions.
1062 Hisashi Iizasa and Kouji Matsushima
GENE AND GENE REGULATION PROTEIN
Accession numbers Accession numbers
See Table 1. See Table 2.
Chromosome location Sequence
4q12-4q21 (human). See Figure 1.
Relevant linkages Description of protein
Chr4. D4S392-D4S2947 (77.9–86cM, human). In human:
pI 8.6
Amino acids size:
Regulatory sites and corresponding
precursor 99
transcription factors mature 69–79 (main form is 72)
Molecular weight of mature form 8
Disulfide bonds 2
The 50 flanking region of the IL-8 gene contains
N-linked glycosylation sites 0
potential binding sites for several transcription fac-
torssuchasAP-1,NF(cid:20)BandNF-IL6(Mukaidaetal.,
1989).NF(cid:20)Bisessentialinmanycelltypes,buteither Discussion of crystal structure
NF-IL6 or AP-1 have to act together with NF(cid:20)B to
activate the IL-8 gene (Matsusaka et al., 1983).
Structural analysis of recombinant IL-8 by NMR
(Clore et al., 1990) and X-ray crystallography
Cells and tissues that express
the gene
Table 2 Accession numbers for IL-8 protein in various
species
IL-8issecretedfromvariouscelltypesduringinflam-
mation. IL-8 has been detected in inflamed tissues
and biofluids in many diseases. Species Accession numbers
Human P10145
Table1 AccessionnumbersforIL-8mRNAandgenesfor Macaques P51495
various species
Sooty mangabey P46653
Bovine P79255
Species mRNA Gene
Sheep P36925
Human Y00787 M28130 Pig P26894
Macaque S78555 Dog P41324
Sooty mangabey U19839 Rabbit P19874
Bovine S82598 AF061521 Guinea pig P49113
Sheep X78306 Chicken P08317
Pig M86923
Dog U10308 D14285
Rabbit M57439 Figure1 AminoacidsequenceforhumanIL-8precursor.
Guinea pig L04986
Human (99 amino acids: precursor):
Chicken X14971 M83361
MTSKLAVALL AAFLISAALC EGAVLPRSAK ELRCQCIKTY SKPFHPKFIK
ELRVIESGPH CANTEIIVKL SDGRELCLDP KENWVQRVVE KFLKRAENS
IL-8 1063
(Baldwin et al., 1990, 1991) revealed that IL-8 is a IL-8 secreted by inflamed tissues is internalized and
dimer at a high concentration. This dimer consists of transported through endothelial cells (Middleton
six (cid:12) strands and two (cid:11) helices of the C-terminal in et al., 1997). The C-terminal end of IL-8 is essential
the antiparallel region. Interestingly, the IL-8 struc- for internalization as well as heparin binding.
ture looks similar to class I major histocompatibility
complex. However, it is not known whether dimer
formation has any physiological significance, since Eliciting and inhibitory stimuli,
the monomer of IL-8 is equally active to neutrophils
including exogenous and
in vitro (Rajarathnam et al., 1994).
endogenous modulators
Important homologies
LPS and inflammatory cytokines induce the produc-
tion of IL-8. These inducers also activate NF(cid:20)B. In
IL-8 is a prototype of the ‘chemokine superfamily’ contrast, IL-4, IL-10, TGF(cid:12), some interferons, and
which consists of over 40 different molecules immunosuppressive drugs such as glucocorticoids,
(Oppenheim et al., 1991). IL-8 belongs to the CXC vitamin D3, and FK506 inhibit the expression of the
chemokine subfamily, which consists of chemokines IL-8 gene (Okamoto et al., 1994) through targeting
nowknownto regulatenotonly migrationof various NF(cid:20)B.
types of leukocytes but also movement of hemato-
poietic progenitor cells and homing of lymphocytes.
The Glu-Leu-Arg (ELR) motif in the N-terminal
region of IL-8 is essential for binding to its receptors RECEPTOR UTILIZATION
(Herbertetal.,1991).Thismotifisalsoimportantfor
neutrophil chemotactic and angiogenic activities in IL-8 binds to two types of receptors, CXCR1 and
other CXC chemokines such as GRO, NAP-2, and CXCR2, which belong to the G protein-coupled
ENA-78, which bind to CXCR2 (Clark-Lewis et al., seven transmembrane receptor superfamily.
1993). Nevertheless, some ELR(cid:255) CXC chemokines,
such as stromal derived factor 1 (SDF-1), inhibit
angiogenesis without the ELR motif.
IN VITRO ACTIVITIES
Posttranslational modifications In vitro findings
Secreted IL-8 is not glycosylated. IL-8 variants are IL-8 is a potent chemoattractant for neutrophils, but
derived by sequential cleavage from the N-terminal invitroIL-8alsoactivatesneutrophilfunctionsuchas
end of the molecule. In vitro, the most prominent release of lysosomal enzymes, generation of super-
activeformofIL-8isthe72aminoacidform.The77 oxide/biolipids, and increases the expression of
amino acid form of endothelial cell-derived IL-8 has adhesion molecules on neutrophils as demonstrated
beenreportedtoonlyinduceapoptosisagainstleuko- by Peveri et al. (1988), Schroder (1989), and Paccaud
cytes (Terui et al., 1998). However, the pathophysio- etal.(1990),respectively.IL-8alsohasbeenshownto
logical role of these variants in vivo remains to be chemoattract basophils, cytokine-stimulated eosino-
established. phils, human peripheral blood T lymphocytes by
Whiteetal.(1989),Warringaetal.(1991),andLarsen
et al. (1989), respectively. Interestingly, IL-8 also
CELLULAR SOURCES AND increases the adhesion of neutrophils to unstimulated
human umbilical cord vein cells but inhibits the
TISSUE EXPRESSION
adhesion of neutrophils to endothelial cells prestimu-
lated by inflammatory cytokines such as IL-1 and
Cellular sources that produce
TNF(cid:11) (Gimbrone et al., 1989).
IL-8 enhances transendothelial migration of neu-
IL-8 is secreted from many cell types, including trophils(Huberetal.,1991),andinducesangiogenesis
monocytes, lymphocytes, granulocytes, fibroblasts, in rat cornea without inducing leukocyte infiltration
endothelial cells, bronchial epithelial cells, keratino- (Koch et al., 1992). These functions of IL-8 suggest
cytes,hepatocytes,mesangialcells,andchondrocytes. important roles of IL-8 in inflammation as well as
1064 Hisashi Iizasa and Kouji Matsushima
host defense (Table 3). On the other hand, IL-8 IN VIVO BIOLOGICAL
enhances viral replication including that of cytome-
ACTIVITIES OF LIGANDS IN
galovirus in human fibroblasts (Murayama et al.,
ANIMAL MODELS
1994) by inhibiting the antiviral activities of IFN(cid:11)
(Khabar et al., 1997).
Normal physiological roles
In many diseases, IL-8 has been detected in inflamed
Bioassays used
tissuesandbiofluids.Theseincludetheskinlesionsof
psoriasis (Schroder and Christophers, 1986), and
IL-8 is measured by neutrophil chemotaxis and
synovialfluidsofrheumatoidarthritis(Brennanetal.,
activation. However, this is not a specific assay since
1990), osteoarthritis (Symons et al., 1992), and gouty
other CXC chemokines also induce migration of
arthritis(Terkeltaubetal.,1991).ElevatedIL-8levels
neutrophils in vitro. To distinguish between the effect
are also detected in other biological fluids such as
of IL-8 and that of other chemokines, monoclonal
bronchoalveolar lavage (BAL) fluids (Carre et al.,
anti-IL-8 antibody is useful.
1991),pleuralfluids(Broaddusetal.,1992)andurine
(Ko et al., 1993) (Table 4). Significant correlations
Table 3 Biological activities of IL-8 in vitro between IL-8 levels and neutrophil infiltration in
diseases has been reported. IL-8 is an essential factor
Target cells Biological activities for acute inflammation. However, recent studies
havedemonstratedthatIL-8isalsoimportantfornon-
Neutrophils Chemotaxis inflammatory reactions. In mice, a functional IL-8
Lysosomal enzyme release homolog, MIP-2, induces migration of neutrophils
into vagina in sexual cycle-dependent manner
Respiratory burst
(Sonoda et al., 1998). In addition, systemic adminis-
Intracellular calcium influx
tration of IL-8 also rapidly induces migration of
Generation of superoxide anion hematopoietic stem cells from bone marrow to peri-
Generation of biolipids pheral blood (Laterveer et al., 1995). These result
(LTB , 15-HETE, etc.) suggest that IL-8 also regulates noninflammatory
4
physiological reaction in vivo.
Induction of expression of
adhesion molecules (CD11a, CD11b,
CD11c, and CD18)
Table 4 Diseases with elevated expression of IL-8
Transendothelial migration
T cells Chemotaxis
Biological fluids Diseases
B cells Inhibition of IL-4-induced IgE
production BAL fluid Acute respiratory distress
syndrome (ARDS)
Basophils Chemotaxis
Idiopathic pulmonary fibrosis
Inhibition of histamine release
Pulmonary edema
Increased leukotriene release
(reperfusion injury)
Monocytes Intracellular calcium influx
Pleural fluid Empyema
Respiratory burst
Urine Urinary tract infection (UTI)
Adhesion
IgA nephropathy
Keratinocytes Proliferation
Acute glomerulonephritis (AGN)
Fibroblasts Decrease of collagen mRNA
Purpuric nephritis
expression
Membranous proliferative
Induction of cytomegalovirus
glomerulonephritis (MGPN)
replication
Lupus nepritis
Endothelial cells Proliferation
Synovial fluids Rheumatoid arthritis
Smooth muscle Chemotaxis
Osteoarthritis
Stem cells Inhibition of colony formation of
myeloid progenitors Gout
IL-8 1065
IL-8 also induces the infiltration of T lymphocytes circulating neutrophils in such IL-8 transgenic mice,
into inflamed tissue. Continuous injection of IL-8 whereas that of bone marrow neutrophils and
caused massive migration of T lymphocytes into neutrophil precursors was normal. In addition, no
injected joints (Kudo et al., 1991). In a delayed type significant upregulation of the (cid:12) integrins level was
2
hypersensitivity reaction model, monoclonal anti- observed on peripheral blood neutrophils in this
IL-8 antibodies reduced the infiltration of both transgenic mouse. These results indicate that IL-8
neutrophils and lymphocytes (Larsen et al., 1995). modulates the surface expression of L-selectin with-
These results suggest that IL-8 also has a significant out showing any effects on (cid:12) -integrin level.
2
role in directly or indirectly regulating the migration
of T lymphocytes in inflammatory reactions.
PATHOPHYSIOLOGICAL ROLES
IN NORMAL HUMANS AND
Species differences
DISEASE STATES AND
DIAGNOSTIC UTILITY
IL-8 homologs in other species have been cloned,
including guinea pigs, sheep (Yoshimura and
Johnson,1993),rabbits(YoshimuraandYuhki,1991), Role in experiments of nature and
pigs(Goodmanetal.,1992),anddogs(Ishikawaetal.,
disease states
1993). However, no clear-cut IL-8 homolog in rat or
mousehasbeenidentifiedsofar,althoughMIP-2and
Thein vitrobiological activitiesofIL-8andincreased
KC may be functional homologs of IL-8 in mice.
production of IL-8 in inflammatory diseases encour-
Furthermore, IL-8 binds to two types of IL-8
aged scientists to administer specific monoclonal
receptors in human, but mouse has only one IL-8
antibodies (mAbs) against IL-8 in animal models of
receptor (homolog of human CXCR2).
acute inflammatory diseases to establish the patho-
physiological role of IL-8 in vivo. In the rabbit lung
Knockout mouse phenotypes reperfusion injury model, administration of anti-IL-8
mAb dramatically blocked tissue injury by inhibiting
neutrophil infiltration into lung tissue in spite of the
Although mice lack an exact homolog of IL-8, the
presenceofotherneutrophilchemoattractantssuchas
oneIL-8receptorthatexists,MuCXCR2,isboundby
complement components (Sekido et al., 1993).
MIP-2 and KC. Gene targeting of CXCR2 in mice
Furthermore, treatment with anti-IL-8 mAb blocked
exhibited inhibition of neutrophil infiltration into
neutrophil infiltration into inflamed tissue, and
inflamed tissue although neutrophil function was
prevented tissue injury in many other animal models
normal (Cacalano et al., 1994). This phenotype is
such as LPS-induced dermatitis (Harada et al., 1993),
similar to blocking of IL-8 activity using anti-IL-8
experimental acute immune complex-induced glomer-
antibodies. However, other neutrophil chemotactic
ulonephritis (Wada et al., 1994), acid aspiration-
factor-related gene knockout mice such as comple-
induced acute respiratory distress syndrome (ARDS)
ment 5a receptor (Hopken et al., 1996) and the
(Folkesson et al., 1995) and cerebral ischemia-
5-lipoxygenase(Gouletet al., 1994)didnotshowany
reperfusion injury (Matsumoto et al., 1997).
impairment of neutrophil influx into inflamed sites.
These data strongly suggest that these classical
chemotactic factors are not important for conven-
IN THERAPY
tional neutrophil infiltration of inflammatory sites,
andthatIL-8isessentialforneutrophilinfiltrationof
Clinical results
inflamed tissues.
HumanizedmonoclonalantibodyagainstIL-8isnow
Transgenic overexpression
in clinical trial by several companies. For example,
Abgenix Inc. (Abgenix) reported an ongoing phase
MicetransfectedtooverexpressIL-8exhibitexcessive I/II clinical trial of anti-IL-8 antibody (they named
accumulation of neutrophils in the microcirculation ABX-IL8) in psoriasis (http://www.abgenix.com).
of the lung, liver, and spleen without neutrophil ABX-IL8 is a completely human antibody derived
infiltration into any tissues, plasma exudation, or fromatransgenicmouseinwhichthemouseantibody
apparent tissue damage (Simonet et al., 1994). L- wasreplacedbyahumanantibodygene.Theyplanto
selectin expression is decreased on the surface of enroll 42 patients with moderate to severe psoriasis.
1066 Hisashi Iizasa and Kouji Matsushima
TheyhavealreadyfinishedaphaseItrialofABX-IL8 into lipopolysaccharide-induced inflammatory site of rabbit
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