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STAT6-Dependent Fashion CCL23 Expression Is Induced by IL-4 in A CCL23 Expression Is Induced by IL-4 in a STAT6-Dependent Fashion Hermann Novak, Anke Müller, Nathalie Harrer, Claudia Günther, Jose M. Carballido and Maximilian Woisetschläger This information is current as of September 28, 2021. J Immunol 2007; 178:4335-4341; ; doi: 10.4049/jimmunol.178.7.4335 http://www.jimmunol.org/content/178/7/4335 Downloaded from References This article cites 47 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/178/7/4335.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CCL23 Expression Is Induced by IL-4 in a STAT6-Dependent Fashion Hermann Novak, Anke Mu¨ller, Nathalie Harrer, Claudia Gu¨nther, Jose M. Carballido, and Maximilian Woisetschla¨ger1 The chemokine CCL23 is primarily expressed in cells of the myeloid lineage but little information about its regulation is available. In this study, it is demonstrated that IL-4 and IL-13 induced CCL23 expression in human peripheral blood monocytes. GM-CSF had no effect on its own but synergized with IL-4, but not IL-13. CCL23 promoter reporter gene constructs were sensitive to IL-4 stimulation in the presence of the transcription factor STAT6. A canonical STAT6 binding site in the promoter region of the CCL23 gene was critical for the IL-4-inducible phenotype because reporter plasmids with a defective STAT6 binding site were unable to respond to IL-4 stimulation. In addition, two tandem copies of the STAT6 site conferred cytokine responsiveness to a heterologous minimal promoter. Furthermore, IL-4 inducibility of the CCL23 promoter was dependent on the absence of a Downloaded from negatively acting cis-element downstream of the STAT6 binding site. The negative function of this element was operative also on heterologous IL-4-inducible promoters. CCL23 was also expressed in skin from patients suffering from atopic dermatitis at higher levels than in normal individuals. However, no correlation between CCL23 expression in the serum and IgE levels as a diagnostic marker for atopy was found. Collectively, these data suggest a link between the inducible phenotype of CCL23 expression in monocytes by the prototype Th2 molecule pair IL-4/STAT6 and the increased number of CCL23-expressing cells in skin of atopic dermatitis patients. The Journal of Immunology, 2007, 178: 4335–4341. http://www.jimmunol.org/ hemokines are small proteins which regulate cell traf- ulation of CCL23 expression. In monocytes, IL-1␤ and IFN-␥, albeit ficking during homeostasis as well as during inflamma- at low levels, induce CCL23 expression (16). Maturation of mono- C tory processes. Chemokine subfamilies have been de- cyte-derived DC with agonistic CD40 Abs or IFN-␥ reduces CCL23 fined classified by the distance between the first two conserved RNA and protein expression. In contrast, treatment of immature DC cysteine residues with the CXC and the CC subfamily containing with IL-10 induces CCL23 production (15). the vast majority of all chemokines. CXC chemokines act mainly A major constituent of the IL-4 signal transduction pathway is on neutrophils and activated T lymphocytes (1), while CC chemo- STAT6 (19, 20). This protein is a transcription factor that resides by guest on September 28, 2021 kines attract a wider number of cell types including monocytes (2, in the cytoplasm of quiescent cells in a latent state. Upon binding 3), lymphocytes (4–6), basophils (7, 8), and eosinophils (9, 10). of IL-4 to its receptor, the ␣-chain of the IL-4R becomes phos- CCL23 (MPIF-1, CK␤8, SCYA23), a member of the CC chemo- phorylated by the tyrosine kinases JAK1 and JAK3. The phos- kine family, was originally isolated from a human aortic endothelial phorylated tyrosine residues on the IL-4R serve as docking sites cell library (11) and from the human monocytic cell line THP-1 (12). for STAT6 molecules. Once recruited to the receptor, STAT6 also It is most closely related to MIP-1␤ and interacts with its receptor becomes phosphorylated by JAKs at a single tyrosine residue. Acti- CCR1, which is expressed on monocytes, dendritic cells (DC),2 lym- vated STAT6 dissociates from the receptor, dimerizes, and translo- phocytes, and endothelial cells. An amino-terminally truncated form cates into the nucleus, where it binds to specific sequences found of CCL23 is also expressed which can also bind to formyl peptide- within promoters of IL-4-regulated genes. STAT6 binding sites have receptor-like 1 receptor (13). Functionally, CCL23 has chemotactic been found in the promoter regions of various IL-4-inducible genes activity for monocytes (12, 14), DC (15, 16), lymphocytes, neutro- such as FIZZ1 (21), CD23 (22), eotaxin-1 (23, 24), eotaxin-3 (25), phils (11), osteoclast precursor cells (17), and endothelial cells (18). In IL-4R (26), and in Ig germline ␧ (27) and ␥-l promoters. The con- contrast, CCL23 reduces the proliferation of progenitor cells giving sensus binding sequence of STAT6 consists of the palindromic TTC Ј Ј rise to granulocyte and monocyte lineages (11), whereas it enhances sequence separated by four nucleotides 5 -TTC(N)4GAA-3 (28). angiogenesis of endothelial cells (18). Little is known about the reg- This study demonstrates that CCL23 production is specifically induced by IL-4 and IL-13 on human monocytes. The activating function of IL-4 is mediated by the STAT6 protein and is depen- Department of Autoimmunity and Transplantation, Novartis Institutes for Biomedical dent on the presence of a STAT6 binding site in the promoter Research, Vienna, Austria region of the CCL23 gene. CCL23-expressing cells are found at Received for publication August 23, 2006. Accepted for publication January 10, 2007. higher frequency in the epidermis of patients suffering from atopic The costs of publication of this article were defrayed in part by the payment of page dermatitis compared with normal individuals. The chemokine was charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. also detectable in plasma of normal and atopic individuals but no 1 Address correspondence and reprint requests to Dr. Maximilian Woisetschla¨ger, correlation with IgE as marker of atopy was found. Department of Autoimmunity and Transplantation, Novartis Institutes for Bio- medical Research, Brunnerstrasse, Vienna, Austria. E-mail address: maximilian. [email protected] Materials and Methods 2 Abbreviations used in this paper: DC, dendritic cell; Ct, cycle threshold; EF1-␣, Cell culture and cytokines elongation factor 1␣. Human primary monocytes were isolated by counterflow centrifugal Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 elutriation (29) from PBMC derived from healthy volunteer donors. The www.jimmunol.org 4336 REGULATION OF CCL23 EXPRESSION IN HUMAN MONOCYTES BY IL-4 purity of these preparations assessed by CD14 staining was typically CCL23p-XEmut were introduced by two sequential PCR as described Ͼ96%. Cells were cultured at a density of 1 ϫ 106/ml in 96-well plates at previously (31) using the mutant primers 5Ј-GAGAATAAATGGGAGT Ј Ј 37°C with 5% CO2 in IMDM supplemented with 2% heat-inactivated FCS TTATTTTTGAAGGAATAATAAGAT-3 and 5 -ATCTTATTATTC (Invitrogen Life Technologies), 100 U/ml penicillin, and 100 ␮g/ml CTTCAAAAATAAACTCCCATTTATTATC-3Ј. Plasmid STAT6mBG streptomycin. was created by ligating a double-stranded oligonucleotide with XhoI/ ␬ ␬ HEK293 cells were cultured at 37°C with 5% CO2 in DMEM supple- BglII overhangs into mBG-LUC NF- B1, replacing the two NF- B mented with 10% heat-inactivated FCS, 100 U/ml penicillin, and 100 sites with two copies of the CCL23 STAT6 site. The sequence of the ␮g/ml streptomycin. Purified human rIL-4 and GM-CSF were obtained oligonucleotides used are: 5Ј-TCGAGATGGGAGTTTTCTTTTGAAG from Novartis and were used at a concentration of 40 and 50 ng/ml, re- GAAATGGGAGTTTTCTTTTGAAGGAAA-3Ј and 5Ј-GATCTTTCCTT spectively. Commercially available IL-13 (PeproTech) was used at 50 ng/ CAAAAGAAAACTCCCATTTCCTTCAAAAGAAAACTCCCATC-3Ј.By ml. LPS (Sigma-Aldrich) was used at 500 ng/ml. a similar strategy, plasmid STAT6mut-mBG was created using the oligonu- cleotides 5Ј-TCGAGATGGGAGTTTATTTTTGAAGGAAATGGGAGTAG ELISA for CCL23 TTTATTTTTGAAGGAAA-3Ј and 5Ј-GATCTTTCCTTCAAAAATAAAC Ј Human CCL23 protein levels were measured with a standard sandwich TCCCATTTCCTTCAAAAATAAACTCCCATC-3 . ELISA. Microtiter wells (Maxisorp Immuno plates; Nunc) were coated The CCL23 promoter-negative regulatory element was cloned as a dou- with 0.5 ␮g/ml anti-human CCL23 Ab MAB371 (R&D Systems) over- ble-stranded oligonucleotide with KpnI/MluI overhangs into the constructs ϩ EOT3 (25) and mBG-LUC NF-␬B1/IL4RE (30) upstream of the STAT6 night at 4°C. Samples were added in different dilutions for 90 min at Ј 37°C. As standard, recombinant CCL23, aa 22–120 was used (R&D Sys- sites using the following sequences: 5 -CCCTTTCCCAGAGACTAAGCGCA GGGCTGAGAAGGA-3Ј and 5Ј-CGCGTCCTTCTCAGCCCTGCGCTTA tems). Afterward, the immune complexes were detected by incubation with Ј 0.5 ␮g/ml biotinylated CCL23 Ab (R&D Systems) for 90 min at 37°C. The GTCTCTGGGAAAGGGGTAC-3 .
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