Department of Medicine, Division of Pulmonary and Critical Care Medicine, Department of Pathology and Laboratory Medicine at the University of California, Los Angeles, School of Medicine, Los Angeles, California 90024-1922
IN THE LAST TWO AND A HALF DECADES,
there has been an explosion of interest in a group of chemotactic
cytokines that have chemotactic activity for leukocytes, now known as
chemokines. Indeed, there have been more than 16,000 publications
related to chemokines since 1975. The human chemokine families are
referred to as CXC, CC, C, and CX3C chemokines. These four
closely related polypeptide families behave, in general, as potent
chemotactic factors for neutrophils, eosinophils, basophils, monocytes,
mast cells, dendritic cells, NK cells, and T and B lymphocytes.
Chemokines in their monomeric form have a molecular mass of 7-10
kDa and are characteristically basic heparin-binding proteins, which
facilitate binding to cells and matrix components within the
lung. The chemokines have in common highly conserved cysteine
amino acid residues. The CXC chemokine family has the first two
NH2-terminal cysteines separated by a single nonconserved
amino acid residue, the CXC cysteine motif, whereas the CC chemokine
family has the first two NH2-terminal cysteines in
juxtaposition, the CC cysteine motif. The C chemokine lymphotactin has
a lone NH2-terminal cysteine amino acid, the C cysteine
motif, and the CX3C chemokine fractalkine has the first two
NH2-terminal cysteines separated by three nonconserved amino acid residues. Interestingly, CXC chemokine genes are, in general, clustered on human chromosome 4, and the proteins exhibit between 20 and 50% homology on the amino acid level, whereas CC chemokine genes are generally clustered on human chromosome 17, and the
proteins exhibit between 28 and 45% homology on the amino acid level.
The gene that encodes lymphotactin is located on human chromosome 1, and the gene encoding fractalkine is located on human chromosome 16. Overall, there is ~20-40% homology between the members of the
four chemokine families.
Although there has been tremendous interest in chemokines for their
ability to recruit specific subpopulations of leukocytes, it is
becoming increasingly clear that the function of these cytokines goes
well beyond leukocyte trafficking. For example, chemokines are involved
in regulating angiogenesis and have direct stimulatory effects on
mesenchyme- and parenchyme-derived cells, and some members of the
chemokine family can exert direct antimicrobial properties similar to
that mediated by human defensins. The varied function/biology of
chemokines can be best exemplified in the lung.
Despite the tremendous interest in chemokines as a whole, the only
chemokine with an interleukin designation is IL-8. According to the new
chemokine nomenclature, IL-8 is now referred to as CXCL8
(11). In fact, of the more than 16,000 publications on chemokines in the last two and half decades, nearly 7,000 of these publications have cited IL-8/CXCL8. IL-8/CXCL8 is a member of the CXC
chemokine family that is also classified by whether a member contains
the three-amino acid sequence of glutamic acid-leucine-arginine (Glu-Leu-Arg, "ELR" motif) that immediately precedes the first cysteine amino acid residue in the primary structure of the protein. The members of the CXC chemokine family that contain this motif are
referred to as ELR + CXC chemokines and have their primary biological effect in promoting neutrophil recruitment and angiogenesis. The gene for IL-8/CXCL8 is found on human chromosome 4, q12-21 (3, 7), and consists of four exons and three introns
(3, 7). The 5'-flanking region of IL-8/CXCL8 contains the
usual "CCAAT" and "TATA" box-like structures. In addition, this
region has a number of potential binding sites for several nuclear
factors (3, 7, 9). The IL-8/CXCL8 promoter region is
regulated in a cell-specific fashion requiring a NF- The promoter region of IL-8/CXCL8 gene has been extensively studied,
but the mechanisms related to signal transduction and optimal
transactivation of the IL-8/CXCL8 gene have required further elucidation. The study by Li and colleagues, the current
article in focus (Ref. 2a, see p. L690 in this
issue), uses human airway epithelial cells to show that
mitogen-activated protein (MAP) kinases are necessary to optimally
induce the gene expression and protein production of IL-8/CXCL8 from
these cells in response to TNF-
ARTICLE
TOP
ARTICLE
REFERENCES
B element plus
either activator protein (AP)-1 or a C/EBP (NF-IL-6) element under
conditions of transcriptional induction with tumor necrosis
factor (TNF)-
or IL-1 (1, 2, 4-6, 8, 10).
Although the IL-8/CXCL8 promoter has two C/EBP (5' and 3') cis elements
with NF-
B nested between them, the 5'-C/EBP element appears to be
the only C/EBP element involved in transcriptional regulation of
IL-8/CXCL8 (1, 2, 4-6, 8, 10). In specific cell
lines, the AP-1 along with NF-
B or C/EBP and NF-
B cis elements
are sufficient for full transcriptional activation of the IL-8/CXCL8
promoter (5, 10). Members of the NF-
B/rel and C/EBP
families of transcriptional factors can interact on a protein:protein
level via the Rel:basic leucine zipper domain of these proteins,
respectively (1, 2, 4, 8). Recently, Wu and associates
(9) examined the basal transcriptional activity of two
epithelial cell lines in which both AP-1 and 5'-C/EBP cis elements bind
protein that markedly transactivates the IL-8/CXCL8 promoter in the
absence of any agonist stimulation. In addition, they demonstrated that
for full transcriptional activation of the promoter there is a
cooperative interaction among all three major cis elements (AP-1,
5'-C/EBP, and NF-
B).
. The investigators demonstrated that
TNF-
activation of the MAP kinases is able to achieve the induction
of IL-8/CXCL8 gene expression and protein production by NF-
B
-dependent, -independent, and posttranscriptional mechanisms. Using
various strategies, they demonstrate that direct inhibition of the MAP
kinases (ERK and JNK) and NF-
B, but not p38, decreased
TNF-
-induced transcription of the IL-8/CXCL8 promoter. They found
that inhibition of JNK signaling reduced TNF-
-induced transcription
of the IL-8 promoter in a NF-
B-dependent manner, whereas inhibition
of ERK impaired TNF-
-induced transcription of the IL-8 promoter in a
NF-
B-independent and AP-1-dependent manner. Finally, they
demonstrated that activation of the MAP kinase p38 is important for
promoting TNF-
-induced IL-8/CXCL8 protein production in a
posttranscriptional manner. Although these studies focused on the role
of TNF-
for the induction of transcription and posttranscriptional
production of IL-8/CXCL8, these findings would also be relevant to
downstream signal transduction events related to activation of
Toll-like receptors and IL-1 type I receptor for the induction of
IL-8/CXCL8 gene expression and protein production. Furthermore,
the study by Li and associates (2a) highlights the fact that multiple
pathways are focused to assure ultimate success in the mediation of
IL-8/CXCL8 gene expression and protein production. This scenario is
relevant to conditions in which the airway epithelium is needed to
respond to pathogen recognition or to react to two of the most
important early response cytokines, TNF-
and IL-1, in the innate
host defense.
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. M. Strieter, Dept. of Medicine, Div. of Pulmonary and Critical Care Medicine, Dept. of Pathology and Laboratory Medicine, UCLA, 900 Veteran Ave., 14-154 Warren Hall, Box 711922, Los Angeles, CA 90024-1922 (E-mail: rstrieter{at}mednet.ucla.edu).
10.1152/ajplung.00146.2002
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REFERENCES |
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1.
Kunsch, C,
Lang RK,
Rosen CA,
and
Shannon MF.
Synergistic transcriptional activation of the IL-8 gene by NF-kappa B p65 (RelA) and NF-IL-6.
J Immunol
153:
153-164,
1994
2.
Kunsch, C,
and
Rosen CA.
NF-kappa B subunit-specific regulation of the interleukin-8 promoter.
Mol Cell Biol
13:
6137-6146,
1993[Abstract].
2a.
Li, J,
Kartha S,
Iasvovskaia S,
Tan A,
Bhat RK,
Manaligod JM,
Page K,
Brasier AR,
and
Hershenson MB.
Regulation of human airway epithelial cell IL-8 expression by MAP kinases.
Am J Physiol Lung Cell Mol Physiol
283:
L690-L699,
2002.
3.
Luster, AD.
Chemokines-chemotactic cytokines that mediate inflammation.
N Engl J Med
338:
436-445,
1998
4.
Matsusaka, T,
Fujikawa K,
Nishio Y,
Mukaida N,
Matsushima K,
Kishimoto T,
and
Akira S.
Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8.
Proc Natl Acad Sci USA
90:
10193-10197,
1993[Abstract].
5.
Mukaida, N,
Mahe Y,
and
Matsushima K.
Cooperative interaction of nuclear factor-kappa B- and cis-regulatory enhancer binding protein-like factor binding elements in activating the interleukin-8 gene by pro-inflammatory cytokines.
J Biol Chem
265:
21128-21133,
1990
6.
Mukaida, N,
Okamoto S,
Ishikawa Y,
and
Matsushima K.
Molecular mechanism of interleukin-8 gene expression.
J Leukoc Biol
56:
554-558,
1994[Abstract].
7.
Rollins, BJ.
Chemokines.
Blood
90:
909-928,
1997
8.
Stein, B,
and
Baldwin AS, Jr.
Distinct mechanisms for regulation of the interleukin-8 gene involve synergism and cooperativity between C/EBP and NF-kappa B.
Mol Cell Biol
13:
7191-7198,
1993[Abstract].
9.
Wu, GD,
Lai EJ,
Huang N,
and
Wen X.
Oct-1 and CCAAT/enhancer-binding protein (C/EBP) bind to overlapping elements within the interleukin-8 promoter. The role of Oct-1 as a transcriptional repressor.
J Biol Chem
272:
2396-2403,
1997
10.
Yasumoto, K,
Okamoto S,
Mukaida N,
Murakami S,
Mai M,
and
Matsushima K.
Tumor necrosis factor alpha and interferon gamma synergistically induce interleukin 8 production in a human gastric cancer cell line through acting concurrently on AP-1 and NF-kB-like binding sites of the interleukin 8 gene.
J Biol Chem
267:
22506-22511,
1992
11.
Zlotnik, A,
and
Yoshie O.
Chemokines: a new classification system and their role in immunity.
Immunity
12:
121-127,
2000[ISI][Medline].