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,
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Johns Hopkins Asthma and Allergy Center and
Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224;
Division of Nephrology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil; and
Department of Medicine, East Tennessee State University, Johnson City, TN
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recent cloning and sequencing studies have demonstrated a family of
IL-17-related genes with potential proinflammatory functions. Human
IL-17 is a T cell-derived, homodimeric protein and exhibits pleiotropic
biological activities (1, 2, 3). IL-17 is able to stimulate
the production of IL-6, IL-8, G-CSF, stem cell factor, and
PGE2 from various cell types, such as
fibroblasts, keratinocytes, and renal epithelial cells
(3, 4, 5, 6, 7). Although the expression of IL-17 is
restricted to activated T cells, the IL-17R is widely expressed. In
addition, elevated IL-17 mRNA expression has been found in mononuclear
cells from patients with multiple sclerosis (8), in
patients with rheumatoid arthritis (9), and in patients
with systemic lupus erythematosus (10), suggesting a role
for IL-17 in the initiation or maintenance of inflammatory responses.
In the airway, IL-17 induces expression of the C-X-C chemokines, IL-8
and macrophage inflammatory protein 2, which selectively recruit
neutrophils into the airway (11). Moreover, IL-17
synergizes, but not by itself, with IFN-
in the induction of ICAM-1
expression on epithelial cells (12); the induction of
ICAM-1 is associated with airway inflammation seen in bronchial asthma
(13).
As part of our ongoing molecular genetic studies of complex diseases, a potential coding region sequence with sequence homology with IL-17 was initially identified from a human genomic DNA clone by the use of bioinformatics tools and sequencing. We describe herein functional characterization of this novel cytokine gene and demonstrate its expression in an inflammatory disease.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To obtain a full-length cDNA sequence, both 5'- and 3'-RACE were performed using cDNAs from activated ragweed allergen-specific T cells as templates. For 3'-RACE, cDNAs were amplified using poly(dT) and a predicted exon sequence primer, 5'-GGCATCATCAATGAAAACCAG-3'. The PCR products were run on 1% low-melting agarose gel, purified using a GeneClean kit (Qbiogene, Carlsbad, CA), and subjected to a nested PCR using an internal sequence primer, 5'-TTCCATGTCACGTAACATCG-3'. After PCR, the products were cloned and sequenced. For 5'-RACE, cDNAs were first tailed with poly(dA) oligonucleotides using TdT enzyme, purified using Sephadex G25 spin columns, and subjected to nested PCRs using poly(dT), a coding region sequence (5'-TCACCAGCACCTTCTCCAAC-3') and an internal sequence (5'-AAGAAACAGAGCAGCCTTGG-3') primer. The PCR products were then cloned and sequenced.
Analysis of tissue distribution, RNA isolation, and cellular expression of ML-1
Tissue distribution data for IL-17 and ML-1 were acquired using
Rapid-Scan gene expression panels for human tissues (OriGene
Technologies, Rockville, MD) according to the manufacturer’s
instructions with 5 mM magnesium and ML-1- and
IL-17-specific primer pairs. The sequences of primers for ML-1 were as
follows: forward, 5'-GGCATCATCAATGAAAACCAG-3'; reverse,
5'-TCACCAGCACCTTCTCCAAC-3'. The sequences of primers for IL-17 were:
forward, 5'-ACTCCTGGGAAGACCTCATTG-3'; reverse,
5'-GGCCACATGGTGGACAATCG-3'. PCR products were visualized by ethidium
bromide-containing gel and photographed. Tissues were graded on a 0–4
grading system based on visualization of bands at the
concentrations of cDNA provided by the manufacturer (++++ = product
obtained with >1 pg/ml; +++ = product obtained with >10 pg/ml; ++ =
product obtained with >100 pg/ml; + = product obtained with 1000
pg/ml; grade 0 = no product obtained with 1000 pg/ml). Appropriate
normalization of cDNA provided by the manufacturer was confirmed by PCR
amplification for the constitutive marker gene, 
-actin.
PBMCs were isolated from the blood of allergic subjects. Peripheral blood CD4+, CD8+ T cells, and monocytes were isolated (>90% purity) from a normal healthy individual using RosetteSep kits from StemCell Technology (Vancouver, Canada) according to the manufacturer’s instruction. Human allergen-specific T cell clones were generated by limiting dilution cloning and subcloning from two atopic subjects, followed by biweekly stimulation of T cells with ragweed allergen extract or purified Amb a 1 (a major ragweed allergen) along with irradiated autologous PBMCs as APCs as described previously (17). The cytokine profiles of T cell clones were determined as described previously (17). Basophils were isolated and purified to homogeneity (>98% purity) following double Percoll density centrifugation and negative selection using a mixture of mAbs (CD2, CD3, CD14, CD16, CD24, CD34, CD36, CD45RA, CD56, glycophorin) and magnetic colloid beads (StemCell Technologies) as described previously (18). Basophils were activated by stimulation with anti-IgE Abs as previously described (18). Human mast cells were generated from umbilical cord blood as described previously (19). Briefly, the mononuclear cell fraction was obtained by centrifugation and suspended in modified DMEM containing 10 µg/ml insulin, 10 µg/ml transferrin, 10 µM 2-ME, 25 mM HEPES, 2.6 ng/ml NaSeO3, 5% FCS, human recombinant stem cell factor at 80 ng/ml (Amgen, Thousand Oaks, CA), human rIL-6 at 50 ng/ml (Amgen), and PGE2 (Sigma, St. Louis, MO) at 300 nM. Cells were used when conformity in morphology and shape of the cells is reached. Purity of mast cells in the preparations was always >95%. Mast cells were activated using myeloma IgE alone (1 µg/ml) or a combination of myeloma IgE (1 µg/ml) and anti-human IgE (1 µg/ml; kindly provided by Dr. R. Hamilton, Johns Hopkins University, Baltimore, MD). Mast cells were sensitized overnight with myeloma IgE at 37°C before challenge with anti-IgE.
ML-1 gene expression was also assayed from bronchoalveolar lavage (BAL)4 cells of four asthmatic patients challenged with either allergen (ragweed, 100 protein nitrogen units) or saline control as described previously (20). The BAL cells were collected 19 h after challenge. Total RNA was isolated from 1) ragweed-activated PBMCs (5 x 106 cells; 6 h after stimulation); 2) peripheral blood CD4+ (1 x 106 cells), CD8+ T cells (5 x 105 cells), and monocytes (1 x 106 cells); all three cell types were stimulated with PMA (100 ng/ml)/ionomycin (2 µg/ml) for 4 h; 3) cloned T cells (2 x 106 cells; 6 h after ragweed allergen stimulation); 4) basophils (2 x 106 cells; 4 h after stimulation); and 5) mast cells (2 x 106 cells; 6 h after stimulation) using RNAzol B according to the manufacturer’s instructions (Tel-Test, Friendswood, TX). cDNAs were synthesized from 500 ng of total RNA in the presence of Moloney murine leukemia virus reverse transcriptase (1 U/reaction; Sigma), oligo(dT) primer, and reaction buffer at 42°C for 90 min, followed by PCR. Each cDNA sample was amplified (30 cycles of 1 min at 95°C, 1 min at 52°C, and 1 min at 72°C) using ML-1 and IL-17 sequence-specific primers (see above). The sequences of primers for a housekeeping gene, G3PDH, were as follows: forward, 5'-ACCACAGTCCATGCCATCAC-3'; reverse, 5'-TCCACCACCCTGTTGCTGTA-3'. The expected size for the ML-1 PCR product is 220 bp, for the IL-17 is 462 bp, and for the G3PDH is 450 bp.
Recombinant ML-1-His fusion proteins
The coding sequence of ML-1 was amplified by PCR and subcloned into the BamHI and XbaI sites of pcDNA 3.1 (Invitrogen, Carlsbad, CA) to generate a C-terminal fusion gene with the His and c-Myc tags. The vector pcDNA 3.1 was transfected into COS-7 cells by an Effectene reagent (Qiagen, Chatsworth, CA) according to the manufacturer’s instructions. Two days after transfection, the supernatants were concentrated over Centricon-10 columns (Amicon, Beverly, MA) and subjected to affinity purification by Ni-NTA agarose beads (Qiagen) for His-tagged proteins. To examine the protein expression, SDS-PAGE analysis was performed on the affinity-purified recombinant proteins under a reducing condition, followed by Western blot analysis using anti-His mAb (Santa Cruz Biotechnology, Santa Cruz, CA).
Analysis of ML-1-induced gene expression
Primary bronchial epithelial (PBE) cells were purchased from Clonetics (San Diego, CA). PBE cells were cultured according to the manufacturer’s instructions. The cells were treated with IL-17 (10 or 100 ng/ml), or ML-1 (10 or 100 ng/ml), or a control His-tagged protein (Positope, 10 or 100 ng/ml; Invitrogen). The affinity-purified control His protein was dissolved in the same buffer as ML-1. Total RNA was extracted using RNeasy (Qiagen) from 1 x 106 cells 4 h after stimulation or exchange of medium. The protocol for cDNA synthesis was the same as described above. For PCR, the sequences of PCR primers were based on the human IL-8 cDNA sequence. The sequences of PCR primers for IL-8 were: forward, 5'-TCTGCAGCTCTGTGTGAAG-3'; reverse, 5'-TAATTTCTGTGTTGGCGCA-3'; IL-6: forward, 5'- ATGAACTCCTTCTCCACAAGCGC-3', reverse, 5'-GAAGAGCCCTCAGGCTGGACTG-3'. Also, gene expression for two chemokines, eotaxin and RANTES, was also analyzed. The primers for eotaxin and RANTES are as follows: eotaxin: forward, 5'-ACAGGAGAATCACCAGTGGC-3', reverse, 5'-ACTTCATGGAATCCTGCACC-3'; RANTES: forward, 5'-CGCTGTCATCCTCATTGCTA-3', reverse, 5'-TGATGTACTCCCGAACCCAT-3'. The amplification reaction was performed for 23 cycles with denaturation at 94°C for 45 s, annealing at 56°C for 45 s, and extension at 72°C for 45 s. PCR products were detected by ethidium bromide staining and normalized by the intensity of an amplified housekeeping gene, G3PDH (see above). The expected size for IL-8 was 154 bp and for IL-6, 628 bp. IL-6 and IL-8 protein levels in the collected supernatants were determined with a commercially available ELISA kit (BioSource International, Camarillo, CA) according to the manufacturer’s instruction.
Analysis of ICAM-1 surface expression by flow cytometry
PBE cells were treated with IL-17 (100 ng/ml), ML-1 (100 ng/ml), or a control His protein (Positope, 100 ng/ml) for 48 h. The cells were harvested following treatment with 0.025% trypsin-0.02% EDTA at 37°C for 6 min and suspended in PBS containing 2% FBS and 0.02% sodium azide. Briefly, 106 cells were incubated with a mouse anti-human ICAM-1 mAb (R&D Systems, Minneapolis, MN) on ice for 30 min. After three washes with PBS, the cells were incubated with FITC-conjugated goat anti-mouse IgG (Bio-Rad, Hercules, CA) on ice for 30 min. After three additional washes with PBS, the cells were resuspended in PBS and immediately analyzed with a FACScan flow cytometer (BD Biosciences, Mountain View, CA). In control samples, staining was performed using isotype-matched control Abs. The mean fluorescence intensity (MFI) was expressed as mean ± SD (n = 5) by subtracting the mean background fluorescence.
Effect of IL-17 on ML-1-induced ICAM-1 gene expression
To assess whether ML-1 interacts with IL-17R, competitive inhibition experiments were performed using the level of ICAM-1 gene expression as a functional readout, since IL-17 by itself is unable to induce ICAM-1 expression. PBE cells were treated with either medium, ML-1 (100 ng/ml) alone, or in combination with varying doses (10–2000 ng/ml) of IL-17 (R&D Systems for 4 h, and total RNAs were extracted from each sample as described above. RT-PCR was performed using the primers based on the human ICAM-1 cDNA sequence. The sequences of primers for ICAM-1 were: forward, 5'-CAGAGGTTGAACCCCACAG-3', reverse, 5'-CCTCTGGCTTCGTCAGAAT-3'. The amplification was performed for 25 cycles with denaturation at 94°C for 45 s, annealing at 55°C for 45 s, and extension at 72°C for 45 s. PCR products were detected by ethidium bromide staining, and normalized by the intensity of an amplified housekeeping gene, G3PDH (see above). The expected size for ICAM-1 was 196 bp.
Data analysis
All data are expressed as mean ± SD. Differences between the groups were analyzed by a one-way ANOVA analysis with the Scheffe F test by using the StatView program (SAS Institute, Cary, NC) on an Apple computer (Apple Computer, Cupertino, CA). Differences were considered to be significant at p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As part of a positional cloning study of a region on chromosome 6p for susceptibility gene discovery for an inherited disease, a potential coding region sequence with homology to human IL-17 was identified from a genomic DNA clone, PAC108C2* (Sanger Center Database, http://www.sanger.ac.uk), using a GenScan prediction program. The predicted expressed sequence with a centromeric-telomeric orientation was composed of 2 exons of 221 and 238 bp, respectively. RT-PCR and sequencing analysis of activated, human allergen-specific T cell clones confirmed the predicted sequence and the splicing sites between the exons. However, the open reading frame utilizes a start codon 129 bp 3' to the predicted start site, encompassing a 92-bp segment in the first exon. A full-length cDNA 947 bp in length was obtained using both 5'- and 3'-RACE, revealing a transcription start site 346 bp upstream of the start codon and a poly(A) sequence 271 bp 3' to the stop codon.
Homology searches using the BLAST program shows a significant degree of
homology between the second exon of the ML-1 gene and the
third exon of IL-17. Alignment of the predicted amino acid sequence of
ML-1 with sequences of IL-17 and the other members of the IL-17 family
shows that while there is the highest overall amino acid sequence
homology (70%) between ML-1 and IL-17, there is only 20% amino acid
identity between ML-1 and the three other family members (Fig. 1
). The alignment shows several conserved
amino acids including a tryptophan residue and four cysteines in the
C-terminal half of the proteins.
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The expression of ML-1 in various cell types and human
tissues was examined using PCR and the Rapid-Scan gene expression
panels for human tissues. Table I shows
the tissue expression of ML-1 and IL-17. ML-1 was strongly expressed in
liver, lung, spleen, placenta, adrenal gland, ovary, and fetal liver.
Interestingly, ML-1 expression in liver, lung, ovary, and fetal liver
was unique when compared with IL-17 (Table I). In addition, although
the expression of ML-1 was not detected in unstimulated cells, with the
exception of mast cells (Fig. 2A), increased ML-1 expression
was clearly evident in six different cell types after activation (Fig. 2B). Those cell types included ragweed allergen-stimulated
PBMCs, ragweed allergen-specific T cell clones with different cytokine
phenotypes (Th0 (clone 12), Th1 (clone 2B7), and Th2 (clone 2D2)),
activated basophils, and activated mast cells (Fig. 2B).
Also, expression of ML-1 was found in activated peripheral blood
CD4+ T cells, but not CD8+
and monocytes (Fig. 2C). In contrast, IL-17 gene
expression was found in only activated peripheral blood
CD4+ T cells, Th0 clones, and PBMCs (Fig. 2).
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C shows representative data demonstrating that while no
detectable expression of ML-1 was seen in the BALs from
saline-challenged sites, ML-1 gene expression was clearly
demonstrated in the BALs from allergen-challenged sites of all four
study subjects. In contrast, no IL-17 transcripts were detected in the
BALs of subjects challenged with allergen (Fig. 2D). Induction of IL-6, IL-8, and ICAM-1 expression in PBE cells
To assess the biological functions of ML-1, His-tagged ML-1
protein was expressed in COS-7 cells and affinity purified (Fig. 3A). PBE cells were treated
with either affinity-purified ML-1 or a His-tagged control protein and
assayed for IL-6, IL-8, and ICAM-1 expression. Similar to IL-17, ML-1
at two different doses, 10 and 100 ng/ml, enhanced IL-6 and IL-8
transcripts (Fig. 3, B and C) and protein
expression for 48 h in PBE cells (Fig. 3, D and
E; for IL-8, 1724.2 ± 132.9 and 4371.4 ± 280.5
pg/ml, respectively; for IL-6, 599.6 ± 19.1 and 1005.3 ±
55.6 pg/ml, respectively). No increase of IL-6 and IL-8 expression was
seen in cells treated with either His-tag control protein or medium
control. Furthermore, ML-1 did not induce the gene expression for two
CC chemokines, eotaxin and RANTES (Fig. 3F).
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for the induction of ICAM-1 expression on
epithelial cells. Up-regulation of ICAM-1 expression is associated with
airway inflammation seen in bronchial asthma (13). To
examine whether ML-1 is able to induce ICAM-1 expression on PBE cells,
surface expression of ICAM-1 on PBE cells was measured and the effects
of ML-1 vs IL-17 were compared. Fig. 4A demonstrates that ICAM-1
was constitutively, but weakly, expressed on PBE cells (MFI =
12.26 ± 1.77) and IL-17 (100 ng/ml) alone did not affect ICAM-1
surface expression at 48 h (MFI = 11.07 ± 1.22). The
supernatants of COS-7 cells alone or in combination with IL-17 did not
induce ICAM-1 expression (data not shown). In contrast, ML-1 (100
ng/ml) significantly induced ICAM-1 expression at 48 h (MFI =
31.42 ± 4.39) (p < 0.05) when compared
with those seen in cells stimulated with IL-17 and a His-tagged protein
(MFI = 12.99 ± 2.09). Furthermore, similar patterns of
differential effects on ICAM-1 gene expression were also
observed (data not shown). These findings suggest a distinct function
of ML-1, despite the fact that IL-17 and ML-1 share a significant
degree of sequence homology. Furthermore, the functional disparity
between IL-17 and ML-1 in the induction of ICAM-1 expression suggests
differential interaction with cellular receptors. To assess whether
ML-1 interacts with IL-17R, competitive inhibition experiments were
performed by measuring the level of ML-1-induced ICAM-1 gene
expression in the presence of varying concentrations of IL-17. As shown
in Fig. 4B, ML-1 at 100 ng/ml markedly induced ICAM-1
expression, and the level of gene expression normalized by the level of
G3PDH expression was not inhibited by the inclusion of IL-17, even at a
20-fold higher dose (2000 ng/ml). These differential biological effects
between ML-1 and IL-17 suggest that these two cytokines may signal via
different cell surface receptors. Further work is needed to identify
the nature of the putative ML-1R.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B; Refs. 1, 2, 3, 21), ML-1 is expressed in
various cell types and tissues. Its distribution is much wider than
that of IL-17, suggesting ML-1 has more biological functions. In
contrast to ML-1 and IL-17, two other members of the IL-17 family,
IL-17B and IL-17C, were not detected in activated
CD4+ T cells (14, 15). Moreover,
among the IL-17 family members, ML-1 shows the highest homology with
human IL-17. It is noted, however, that contrary to a previous report,
the IL-17 gene is localized on the same genomic DNA clone
(GenBank accession no. AL391221) 
50 kb telemeric to ML-1
sequence and both genes are in a tail-to-tail orientation (data not
shown), suggesting a potential gene duplication event.
Two other members of the IL-17 gene family, IL-17B and
IL-17C, each share 27% amino acid identity with IL-17 (14, 15). IL-17B mRNA is expressed in adult pancreas, small
intestine, and stomach, whereas IL-17C mRNA is not detected in the same
set of adult tissues. Interestingly, no expression of IL-17B or IL-17C
mRNA is found in activated T cells (15). Both IL-17B and
IL-17C stimulate the release of TNF and IL-1 from a monocytic cell
line, THP-1. However, IL-17B and IL-17C are not able to stimulate IL-6
production from human fibroblasts and do not bind to the human IL-17R.
Furthermore, a newly discovered member of the IL-17 gene
family, IL-17E, has been shown to induce activation of NF-
B and IL-8
via a distinct receptor (16). Taken together, these
results and other published studies suggest the existence of a family
of IL-17-related cytokines differing in their patterns of tissue/cell
expression and in their potential roles in immunologic responses.
ML-1 and IL-17 showed the same potency in the induction of IL-6 and IL-8, suggesting that ML-1 is involved in neutrophil recruitment into the airway such as IL-17 (11). The level of IL-8 is increased in inflammatory airway diseases, such as bronchial asthma, chronic obstructive pulmonary disease, and cystic fibrosis (22, 23, 24). There is a strong correlation between the level of IL-8 and the increase in neutrophil numbers (22). An anti-IL-8 mAb inhibited neutrophil chemotaxis in patients with chronic obstructive pulmonary disease or cystic fibrosis (24). In addition, bronchial epithelial cells are an important cell source of IL-8 and may thereby control neutrophil influx in the airway (25). Therefore, IL-8 release in bronchial epithelial cells may play a crucial role in modulating neutrophil-associated airway inflammation.
Although IL-17 and ML-1 induce IL-8 expression from PBE cells, IL-17
fails to induce ICAM-1 expression in human bronchial epithelial cells
(Fig. 4A and Ref. 12). By comparison, ML-1
markedly induced ICAM-1 expression. It has been shown that ICAM-1
expression is increased in airway diseases, such as bronchial asthma
(13). In particular, a high level of ICAM-1 expression,
along with inflammatory cell infiltration, has been demonstrated in
bronchial biopsies from both stable asthmatics and subjects after
allergen challenge (13, 26). Moreover, allergen challenge
up-regulated ICAM-1 expression in airway epithelium, correlating with
eosinophil infiltration. Increased expression of ML-1, but not IL-17,
is also seen in patients with asthma following allergen challenge.
Moreover, expression of ML-1 is detected in activated Th2 cells,
basophils, and mast cells, three important cell types involved in
allergic responses. These findings suggest, therefore, that ML-1 may be
involved in the expression of airway inflammation by, at least in part,
facilitating leukocyte recruitment and activation via the induction of
IL-8 and ICAM-1 in airway epithelium. Further investigation is
necessary to clarify the mechanism(s) by which ML-1 is involved in
normal physiology, asthma, and other inflammatory diseases.
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Acknowledgments |
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Footnotes |
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2 M.K. and L.F.O. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Shau-Ku Huang, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224-6801. E-mail address: skhuang{at}mail.jhmi.edu
4 Abbreviations used in this paper: BAL, bronchoalveolar lavage; PBE, primary bronchial epithelial; MFI, mean fluorescence intensity.
Received for publication May 14, 2001. Accepted for publication August 9, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and interleukin-4-induced activation of human keratinocytes. J. Invest. Dermatol. 115:81.[Medline]
1-integrins in asthma. Eur. Respir. J. 7:1439.[Abstract]
and tumour necrosis factor-
. Immunology 77:330.[Medline]
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M. Kawaguchi, L. F. Onuchic, and S.-K. Huang Activation of Extracellular Signal-regulated Kinase (ERK)1/2, but Not p38 and c-Jun N-terminal Kinase, Is Involved in Signaling of a Novel Cytokine, ML-1 J. Biol. Chem., May 3, 2002; 277(18): 15229 - 15232. [Abstract] [Full Text] [PDF]
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