HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Raes, G. Articles by Sozzani, S. Search for Related Content PubMed PubMed Citation Articles by Raes, G. Articles by Sozzani, S. Pubmed/NCBI databases Substance via MeSH

Arginase-1 and Ym1 Are Markers for Murine, but Not Human, Alternatively Activated Myeloid Cells

Laboratory of Cellular and Molecular Immunology, Department of Molecular and Cellular Interactions, Vlaams Interuniversitair Instituut voor Biotechnologie, Vrije Universiteit Brussel, Brussels, Belgium

In an interesting paper, Scotton et al. (1) reported the effects of IL-13 on the transcriptional profile of human monocytes. Comparing their results with studies analyzing the profile induced by IL-4 in murine macrophages (2, 3), the authors notice some differences, giving as examples up-regulation of Ym1 and arginase-1 in murine macrophages, but not in human monocytes. The authors suggest these differences reflect the fact that IL-4 and IL-13 are highly similar, yet different molecules. Besides overlapping effects with IL-4, IL-13 indeed has documented nonredundant functions and effects (4, 5). However, when comparing results obtained in murine macrophages to human monocytes, differences between monocytes and differentiated macrophages, as well as interspecies differences, may be involved. Indeed, human monocytes and monocyte-derived macrophages exhibit differences in their response to IL-4 and IL-13 (6). Moreover, we and others recently documented that, similar to IL-13, IL-4 does not induce arginase-1 in human monocytes and monocyte-derived macrophages (7, 8), in contrast to murine macrophages, where the arginine metabolism is even one of the discriminative criteria between so-called alternatively and classically activated macrophages (9). Furthermore, in human monocytes, under conditions inducing mannose receptor and macrophage galactose-type C-type lectin, markers for IL-4/IL-13-induced, alternatively activated macrophages (7), we have not detected induction by IL-4 and IL-13 of eosinophil chemotactic cytokine, the closest human homolog of mouse Ym1 by sequence identity (Fig. 1). Overall, next to similarities, murine and human alternatively activated myeloid cells exhibit distinct differences. These should be taken into consideration to make optimal use of information obtained from murine models, and to relate it to the human situation.

View larger version (11K): [in this window] [in a new window]   FIGURE 1. In vitro cytokine modulation of ARG1 (Arginase, type I), CHIA (eosinophil chemotatic cytokine), CLEC10A (human macrophage galactose-type C-type lectin), and MRC (mannose receptor, C type 1) expression in human monocytes. Monocytes were isolated from buffy coats of healthy volunteer blood donors and treated with IL-4 plus IL-13 (15 ng/ml each) for 48 h as described (7 ). Gene expression was determined via quantitative RT-PCR and normalized for the housekeeping gene GAPDH. Fold induction of the genes is shown as compared with the no-treatment control (incubated in vitro in the absence of cytokines). Data are shown for one representative experiment. *, Significantly higher than no treatment (p < 0.05). The error bars indicate the SEM.

References

1. Scotton, C. J., F. O. Martinez, M. J. Smelt, M. Sironi, M. Locati, A. Mantovani, S. Sozzani. 2005. Transcriptional profiling reveals complex regulation of the monocyte IL-1 system by IL-13. J. Immunol. 174: 834-845.[Abstract/Free Full Text]
2. Welch, J. S., L. Escoubet-Lozach, D. B. Sykes, K. Liddiard, D. R. Greaves, C. K. Glass. 2002. TH2 cytokines and allergic challenge induce Ym1 expression in macrophages by a STAT6-dependent mechanism. J. Biol. Chem. 277: 42821-42829.[Abstract/Free Full Text]
3. Loke, P., M. G. Nair, J. Parkinson, D. Guiliano, M. Blaxter, J. E. Allen. 2002. IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype. BMC Immunol. 3: 7.[Medline]
4. Mohrs, M., B. Ledermann, G. Köhler, A. Dorfmüller, A. Gessner, F. Brombacher. 1999. Differences between IL-4- and IL-4 receptor -deficient mice in chronic leishmaniasis reveal a protective role for IL-13 receptor signaling. J. Immunol. 162: 7302-7308.[Abstract/Free Full Text]
5. McKenzie, G. J., P. G. Fallon, C. L. Emson, R. K. Grencis, A. N. McKenzie. 1999. Simultaneous disruption of interleukin (IL)-4 and IL-13 defines individual roles in T helper cell type 2-mediated responses. J. Exp. Med. 189: 1565-1573.[Abstract/Free Full Text]
6. Hart, P. H., C. S. Bonder, J. Balogh, H. L. Dickensheets, R. P. Donnelly, J. J. Finlay-Jones. 1999. Differential responses of human monocytes and macrophages to IL-4 and IL-13. J. Leukocyte Biol. 66: 575-578.[Abstract]
7. Raes, G., L. Brys, B. K. Dahal, J. Brandt, J. Grooten, F. Brombacher, G. Vanham, W. Noel, P. Bogaert, T. Boonefaes, et al 2005. Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation. J. Leukocyte Biol. 77: 321-327.[Abstract/Free Full Text]
8. Munder, M., F. Mollinedo, J. Calafat, J. Canchado, C. Gil-Lamaignere, J. M. Fuentes, C. Luckner, G. Doschko, G. Soler, K. Eichmann, et al 2004. Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity. Blood 105: 2549-2556.
9. Munder, M., K. Eichmann, M. Modolell. 1998. Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4⁺ T cells correlates with Th1/Th2 phenotype. J. Immunol. 160: 5347-5354.[Abstract/Free Full Text]

The Authors Respond

Chris Scotton^*, Massimo Locati, Alberto Mantovani^, and Silvano Sozzani^,

^* Centre for Respiratory Research, University College London, Rayne Institute, London, United Kingdom Section of General Pathology, University of Milan, Milan, Italy Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy Section of General Pathology and Immunology, University of Brescia, Brescia, Italy

In a recent paper, we reported the transcriptional profile induced by IL-13 in human monocytes (R1 ). We described that in monocytes, IL-13 regulates 142 genes, 85 of which were increased and 57 decreased. The majority of these genes were related to the inflammatory response, innate immunity, and lipid metabolism. Regulated genes included characteristic markers of alternatively activated macrophages, such as the mannose receptor (MRC1), CD23 (FCER2, FcR for IgE), CCL22 (also known as MDC), arachidonate 15-lipoxygenase (ALOX15), IL-1RII, IL-1Ra, and a number of novel genes (R1 ).Genes such as Ym1 and Arginase, which are known to be regulated by IL-4 in murine macrophages (R2 R3 ), were not detected in our study. We speculated that these differences may reflect the fact that IL-4 and IL-13 are highly similar yet different molecules (R4 R5 ).

In their letter, Raes and colleagues comment on additional factors that may explain differences in the IL-4 and IL-13 gene profiles, including differences related to the type of cells investigated (e.g., blood monocytes vs differentiated macrophages) or related to the species investigated (i.e., human vs mouse). We completely agree with Raes and colleagues, and we also believe that multiple factors may be responsible for the discrepancies reported (R1 ) and different explanations might be found for any single gene investigated. In relation to the differential induction of Arginase in our experimental conditions and those reported by others (R2 R3 ), it is likely that the explanation is in the interspecies differences between human cells and mouse macrophages. In fact, in a gene profile of human monocytes, monocyte-derived dendritic cells and monocyte-derived macrophages polarized to the M1 phenotype (LPS or immunocomplexes) or the M2 phenotype (IL-4 or IL-13) (R6 ), we also have not found an up-regulation of Arginase (our unpublished observations). An integrated analysis of the transcriptomes in different experimental conditions will provide further evidence on the level of regulation of monocyte and macrophage-regulated genes. Therefore, we certainly agree with the note of caution that Raes and colleagues have pointed out.

References

1. Scotton, C. J., F. O. Martinez, M. J. Smelt, M. Sironi, M. Locati, A. Mantovani, S. Sozzani. 2005. Transcriptional profiling reveals complex regulation of the monocyte IL-1 system by IL-13. J. Immunol. 174: 834-845.
2. Welch, J. S., L. Escoubet-Lozach, D. B. Sykes, K. Liddiard, D. R. Greaves, C. K. Glass. 2002. TH2 cytokines and allergic challenge induce Ym1 expression in macrophages by a STAT6-dependent mechanism. J. Biol. Chem. 277: 42821-42829.
3. Loke, P., M. G. Nair, J. Parkinson, D. Guiliano, M. Blaxter, J. E. Allen. 2002. IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype. BMC Immunol. 3: 7.
4. McKenzie, G. J., P. G. Fallon, C. L. Emson, R. K. Grencis, A. N. McKenzie. 1999. Simultaneous disruption of interleukin (IL)-4 and IL-13 defines individual roles in T helper cell type 2-mediated responses. J. Exp. Med. 189: 1565-1573.
5. Mohrs, M., B. Ledermann, G. Köhler, A. Dorfmüller, A. Gessner, F. Brombacher. 1999. Differences between IL-4- and IL-4 receptor -deficient mice in chronic leishmaniasis reveal a protective role for IL-13 receptor signaling. J. Immunol. 162: 7302-7308.
6. Mantovani, A., S. Sozzani, M. Locati, P. Allavena, A. Sica. 2002. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23: 549-555.[Medline]

This article has been cited by other articles:

				C. Porta, M. Rimoldi, G. Raes, L. Brys, P. Ghezzi, D. Di Liberto, F. Dieli, S. Ghisletti, G. Natoli, P. De Baetselier, et al. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor {kappa}B PNAS, September 1, 2009; 106(35): 14978 - 14983. [Abstract] [Full Text] [PDF]

				R. Shaykhiev, A. Krause, J. Salit, Y. Strulovici-Barel, B.-G. Harvey, T. P. O'Connor, and R. G. Crystal Smoking-Dependent Reprogramming of Alveolar Macrophage Polarization: Implication for Pathogenesis of Chronic Obstructive Pulmonary Disease J. Immunol., August 15, 2009; 183(4): 2867 - 2883. [Abstract] [Full Text] [PDF]

				C. Kadoch, E. B. Dinca, R. Voicu, L. Chen, D. Nguyen, S. Parikh, J. Karrim, M. A. Shuman, C. A. Lowell, P. A. Treseler, et al. Pathologic Correlates of Primary Central Nervous System Lymphoma Defined in an Orthotopic Xenograft Model Clin. Cancer Res., March 15, 2009; 15(6): 1989 - 1997. [Abstract] [Full Text] [PDF]

				S. Fruchon, M. Poupot, L. Martinet, C.-O. Turrin, J.-P. Majoral, J.-J. Fournie, A.-M. Caminade, and R. Poupot Anti-inflammatory and immunosuppressive activation of human monocytes by a bioactive dendrimer J. Leukoc. Biol., March 1, 2009; 85(3): 553 - 562. [Abstract] [Full Text] [PDF]

				I. S. Junttila, K. Mizukami, H. Dickensheets, M. Meier-Schellersheim, H. Yamane, R. P. Donnelly, and W. E. Paul Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4R{alpha}, IL-13R{alpha}1, and {gamma}c regulates relative cytokine sensitivity J. Exp. Med., October 27, 2008; 205(11): 2595 - 2608. [Abstract] [Full Text] [PDF]

				S. Garrett, K. Dietzmann-Maurer, L. Song, and K. E. Sullivan Polarization of Primary Human Monocytes by IFN-{gamma} Induces Chromatin Changes and Recruits RNA Pol II to the TNF-{alpha} Promoter J. Immunol., April 15, 2008; 180(8): 5257 - 5266. [Abstract] [Full Text] [PDF]

				V. Bourlier, A. Zakaroff-Girard, A. Miranville, S. De Barros, M. Maumus, C. Sengenes, J. Galitzky, M. Lafontan, F. Karpe, K.N. Frayn, et al. Remodeling Phenotype of Human Subcutaneous Adipose Tissue Macrophages Circulation, February 12, 2008; 117(6): 806 - 815. [Abstract] [Full Text] [PDF]

				Z. V. Popovic, R. Sandhoff, T. P. Sijmonsma, S. Kaden, R. Jennemann, E. Kiss, E. Tone, F. Autschbach, N. Platt, E. Malle, et al. Sulfated Glycosphingolipid as Mediator of Phagocytosis: SM4s Enhances Apoptotic Cell Clearance and Modulates Macrophage Activity J. Immunol., November 15, 2007; 179(10): 6770 - 6782. [Abstract] [Full Text] [PDF]

				F. O. Martinez, S. Gordon, M. Locati, and A. Mantovani Transcriptional Profiling of the Human Monocyte-to-Macrophage Differentiation and Polarization: New Molecules and Patterns of Gene Expression J. Immunol., November 15, 2006; 177(10): 7303 - 7311. [Abstract] [Full Text] [PDF]

				A. Erdely, D. Kepka-Lenhart, M. Clark, P. Zeidler-Erdely, M. Poljakovic, W. J. Calhoun, and S. M. Morris Jr Inhibition of phosphodiesterase 4 amplifies cytokine-dependent induction of arginase in macrophages Am J Physiol Lung Cell Mol Physiol, March 1, 2006; 290(3): L534 - L539. [Abstract] [Full Text] [PDF]

				R. G. Boot, A. P. Bussink, and J. M. F. G. Aerts Human Acidic Mammalian Chitinase Erroneously Known as Eosinophil Chemotactic Cytokine Is Not the Ortholog of Mouse Ym1 J. Immunol., August 15, 2005; 175(4): 2041 - 2042. [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Raes, G. Articles by Sozzani, S. Search for Related Content PubMed PubMed Citation Articles by Raes, G. Articles by Sozzani, S. Pubmed/NCBI databases Substance via MeSH