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Th2-Associated Expression Pattern with a Α of Macrophage Alternative Macrophage Activation-Associated CC-Chemokine-1, a Novel Structural Homologue of Macrophage Inflammatory Protein-1α with a Th2-Associated Expression Pattern This information is current as of September 29, 2021. Vitam Kodelja, Carola Müller, Oliver Politz, Nahid Hakij, Constantin E. Orfanos and Sergij Goerdt J Immunol 1998; 160:1411-1418; ; http://www.jimmunol.org/content/160/3/1411 Downloaded from References This article cites 52 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/160/3/1411.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on September 29, 2021 *average 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 © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Alternative Macrophage Activation-Associated CC-Chemokine-1, a Novel Structural Homologue of Macrophage Inflammatory Protein-1a with a Th2-Associated Expression Pattern1 Vitam Kodelja, Carola Mu¨ller, Oliver Politz, Nahid Hakij, Constantin E. Orfanos, and Sergij Goerdt2 We have cloned a novel human CC-chemokine, alternative macrophage activation-associated CC-chemokine (AMAC)-1. The isolated cDNA clone (803 bp) shows a single open reading frame of 267-bp coding for 89 amino acid residues; mature AMAC-1 protein is predicted to consist of 69 amino acids with a m.w. of 7855. Sequence alignment and 3D-modeling show the typical Downloaded from structural characteristics of CC-chemokines with special features in the receptor-activating domain. AMAC-1 is most closely related to MIP-1a with a cDNA and protein sequence homology of 55% and 59%, respectively. However, the expression pattern of AMAC-1 is directly opposite to that of MIP-1a. While MIP-1a is induced by classical macrophage mediators such as LPS and is inhibited by IL-4 and glucocorticoids, AMAC-1 is specifically induced in macrophages by alternative macrophage mediators such as IL-4, IL-13, and IL-10. Expression of AMAC-1 is inhibited by IFN-g while glucocorticoids exert a slightly positive synergistic effect in combination with IL-4. Peripheral blood monocytes do not express AMAC-1; time course experiments show http://www.jimmunol.org/ that monocyte-to-macrophage differentiation is a prerequisite for AMAC-1 expression. Expression of AMAC-1 by granulocyte-- macrophage CSF/IL-4-induced, monocyte-derived dendritic cells is complex; in mature adherent dendritic cells, however, only minor AMAC-1 mRNA expression was found. In vivo, AMAC-1 is expressed by alveolar macrophages from healthy persons, smokers, and asthmatic patients. In conclusion, AMAC-1 is a novel CC-chemokine whose expression is induced in alternatively activated macrophages by Th2-associated cytokines; thus, AMAC-1 may be involved in the APC-dependent T cell development in inflammatory and immune reactions. The Journal of Immunology, 1998, 160: 1411–1418. he concept of Th2-associated alternative immunologic inhibited by IFN-g. Furthermore, expression and synthesis of by guest on September 29, 2021 macrophage activation was introduced in 1992 by Stein et proinflammatory cytokines such as IL-1 (6, 7), IL-6 (8), and T al. (1). In contrast to classical macrophage activation by TNF-a (6, 7) are inhibited by IL-4. In contrast, IL-4 and IFN-g IFN-g and LPS, activation of macrophages by agents such as IL-4 sometimes exert synergistic effects such as accumulation of cyto- or glucocorticoids (GCs),3 was classified as alternative. Besides plasmic CD23 (9) or inhibition of CD14 expression (10). Vice IFN-g and IL-4, macrophage activation and differentiation is in- versa, GC effects on macrophages are sometimes antagonistic to fluenced by other cytokines. The effects of TNF-a and IL-12 par- IL-4; in contrast to IL-4, GCs, for example, inhibit macrophage tially overlap with those of IFN-g. IL-10 and IL-13 resemble IL-4, expression of CD23 (9, 11). In general, IL-4-induced inflammatory b g while TGF- acts similarly to GC. Nevertheless, IFN- and IL-4 macrophages adopt an alternative phenotype characterized by a are the agents best known to exert a wide range of antagonistic high capacity for endocytic clearance and by reduced proinflam- effects on macrophages; for example, expression of the three spe- matory cytokine secretion (1). g g cies of Fc Rs (2, 3) is induced by IFN- , but is inhibited by IL-4. In previous reports, we have shown that MS-1 high m.w. On the other hand, expression of the macrophage mannose recep- protein (MS-1-HMWP) (9, 12–14) and RM 3/1 Ag (15, 16) tor (1, 4) and of 15-lipoxygenase (5) is induced by IL-4, but is characterize alternative macrophage phenotypes (17) in that their expression is induced by IL-4 and GC and inhibited by IFN-g (9, 18). In vivo, MS-1-HMWP1,RM3/11 alternatively Klinik und Poliklinik fu¨r Dermatologie, Universita¨tsklinikum Benjamin Franklin, activated macrophages are found during the healing phase of Freie Universitat Berlin, Berlin, Germany acute inflammatory reactions (19), in chronic inflammatory dis- Received for publication September 2, 1997. Accepted for publication October 20, 1997. eases such as rheumatoid arthritis (20) and psoriasis (21), and in The costs of publication of this article were defrayed in part by the payment of page wound healing tissue (9). In addition, alternatively activated charges. This article must therefore be hereby marked advertisement in accordance macrophages are the cells of origin in cutaneous macrophage- with 18 U.S.C. Section 1734 solely to indicate this fact. derived tumors (14, 18). In contrast to IFN-g-induced classi- 1 This work was supported by the Deutsche Forschungsgemeinschaft through grants cally-activated macrophages that occur during early phases of to S. G. (Go 470/2-1 and -2). inflammation (19) and in high turnover reactive granulomas 2 Address correspondence and reprint requests to Professor S. Goerdt, Klinik und Poliklinik fu¨r Dermatologie, Universita¨tsklinikum Benjamin Franklin, Freie Univer- (14, 18, 22), alternatively activated macrophages are associated sita¨t Berlin, Berlin, Germany. with a high degree of vascularization in vivo (9, 14, 18) and 3 Abbreviations used in this paper: GC, glucocorticoids; MS-1-HMWP, MS-1 high seem to be angiogenic in vitro (23). Furthermore, alternatively m.w. protein; AMAC-1, alternative macrophage activation-associated CC-chemo- activated macrophages do not costimulate, but actively inhibit kine; MIP, macrophage inflammatory protein; GM-CSF, granulocyte-macrophage 1 CSFpfu, plaque-forming units. mitogen-induced proliferation of PBL and CD4 T cells by an Copyright © 1998 by The American Association of Immunologists 0022-1767/98/$02.00 1412 AMAC-1-CC-CHEMOKINE FROM ALTERNATIVELY ACTIVATED MACROPHAGES unknown mechanism (24). Therefore, we reasoned that alter- Germany); human recombinant macrophage CSF (M-CSF), used at 100 natively activated macrophages may host a not yet fully unrav- U/ml, was from Cellular Products (Buffalo, NY); human rIL-4, used at 15 eled molecular repertoire important in modulating diverse in- ng/ml for induction of alternative macrophage differentiation and at 45 ng/ml for derivation of dendritic cells from monocytes, was from Serva flammatory and immune responses. (Heidelberg, Germany); human rIL-10, used at 50 ng/ml, was from Biomol Here, we report the identification, cloning, and expression anal- (Hamburg, Germany). Dexamethasone, used at 5 3 1027 M or as indi- ysis of a novel CC-chemokine, alternative macrophage activation- cated, and LPS from Escherichia coli serotype 055:B5, used at 25 mg/ml, associated CC-chemokine (AMAC)-1, induced by Th2-associated were from Sigma. cytokines such as IL-4, IL-13, and IL-10 in alternatively activated Isolation of cDNA clones macrophages in vivo and found in alveolar macrophages in vitro. Total RNA from alternatively activated macrophages was isolated using Stratagene isolation kits. The poly(A)1 fraction was separated with Oli- Materials and Methods gotex-dT (Qiagen, Hilden, Germany) and 2 mg were used for synthesis of Tissues, cells, and cell lines cDNA library using lZAP Express EcoRI/XhoI vector cloning kit (Strat- agene, Heidelberg, Germany). The library consisted of 1.2 3 105 original Skin and bowel specimens were taken at routine surgery and bronchoal- clones, 86% of which contained inserts. This first cDNA library was am- veolar lavage cells were harvested at routine BAL after informed consent plified up to a titer of 2.5 3 108 pfu/ml. The resultant alternatively acti- was obtained. Cell lines used were monocytic leukemia cell line THP-1 and vated macrophage cDNA library and a commercially available human melanoma cell line MEWO cultured in RPMI 1640 supplemented with spleen cDNA library (lgt10, Clontech, Heidelberg, Germany) were differ- 10% FCS (Biochrom, Berlin, Germany) and appropriate concentrations of entially screened as follows. penicillin/streptomycin, glutamine, and nonessential amino acids
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