Key Points
-
Macrophages are a heterogeneous population of resident and recruited cells that are found in all organs and are involved in tissue homeostasis and defence of the host.
-
The cells express a wide range of surface receptors, which mediate their recognition of endogenous and microbial ligands.
-
Activation of macrophages by surface ligands and cytokines induces a spectrum of pro- and anti-inflammatory states, which are responsible for immune activation and deactivation.
-
The T helper 2 (TH2) cytokines interleukin-4 (IL-4) and IL-13 induce a characteristic, stereotypical, 'alternative' activation state of macrophages that is distinct from the 'classical' TH1-type activation by interferon-γ and deactivation by IL-10 and transforming growth factor-β.
-
The effects of IL-4 and IL-13 on macrophages contribute to clearance, presentation of antigens and repair in allergic immune reactions and parasite-induced granuloma formation.
-
Useful markers of alternative macrophage activation include induction of expression of the mannose receptor, MHC class II molecules and selected chemokines, as well as new gene products that have been discovered by gene-expression studies.
-
In this review, I argue for a more limited definition of alternative activation by IL-4 and IL-13, which act through a common receptor subunit, and I distinguish this form of activation from other forms of immunomodulation.
-
This model lends itself to further study of macrophages by gene profiling and proteomics, and it might become extended to a range of other forms of modified immune responses, with potential therapeutic benefits.
Abstract
The classical pathway of interferon-γ-dependent activation of macrophages by T helper 1 (TH1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the TH2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Mackaness, G. B. The immunological basis of acquired cellular resistance. J. Exp. Med. 120, 105 (1964). An early delineation of macrophage activation by intracellular infection.
Gordon, S. in Fundamental Immunology 4th edn Ch. 15 (ed. Paul, W.) 533–545 (Lippincott Raven, Philadelphia, 1999).
Gordon, S. in Immunology 6th edn (eds Roitt, I., Brostoff, B. & Male, D.) 147–162 (Mosby, Edinburgh, 2001).
Hamilton, T. in The Macrophage 2nd edn (eds Burke, B. & Lewis, C. E.) 73–102 (Oxford Univ. Press, 2002).
Dalton, D. K. et al. Multiple defects of immune-cell function in mice with disrupted interferon-γ genes. Science 259, 1739–1742 (1993). The definitive proof that IFN-γ is a 'classical activator' of macrophage anti-microbial activity and is an inducer of the expression of MHC class II molecules and NOS2.
Ehrt, S. et al. Reprogramming of the macrophage transcriptome in response to interferon-γ and Mycobacterium tuberculosis. Signaling roles of nitric oxide synthase-2 and phagocyte oxidase. J. Exp. Med. 194, 1123–1140 (2001).
Boldrick, J. C. et al. Stereotyped and specific gene-expression programs in human innate immune responses to bacteria. Proc. Natl Acad. Sci. USA 99, 972–977 (2002).
Nau, G. J. et al. Human macrophage activation programs induced by bacterial pathogens. Proc. Natl Acad. Sci. USA 99, 1503–1508 (2002).
Goerdt, S. & Orfanos, C. E. Other functions, other genes: alternative activation of antigen-presenting cells. Immunity 10, 137–142 (1999).
Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J. & Hill, A. M. M-1/M-2 macrophages and the TH1/TH2 paradigm. J. Immunol. 164, 6166–6173 (2000).
Tzachanis, D., Berezovskaya, A., Nadler, L. M. & Boussiotis, V. A. Blockade of B7/CD28 in mixed lymphocyte reaction cultures results in the generation of alternatively activated macrophages, which suppress T-cell responses. Blood 99, 1465–1473 (2002).
Peiser, L., Mukhopadhyay, S. & Gordon, S. Scavenger receptors in innate immunity. Curr. Opin. Immunol. 14, 123–128 (2002).
Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2 and PAF. J. Clin. Invest. 101, 890–898 (1998).
Ravetch, J. V. & Bolland, S. IgG Fc receptors. Annu. Rev. Immunol. 19, 275–290 (2001).
Barrington, R., Zhang, M., Fischer, M. & Carroll, M. C. The role of complement in inflammation and adaptive immunity. Immunol. Rev. 180, 5–15 (2001).
Crouch, E. C. & Whitsett, J. A. in Innate Immunity (eds Ezekowitz, R. A. B. & Hoffman, J. A.) 205–229 (Humana, Totowa, New Jersey, 2002).
Tobias, P. A. in Innate Immunity (eds Ezekowitz, R. A. B. & Hoffman, J. A.) 255–265 (Humana, Totowa, New Jersey, 2002).
Kaisho, T. & Akira, S. in Innate Immunity (eds Ezekowitz, R. A. B. & Hoffman, J. A.) 177–189 (Humana, Totowa, New Jersey, 2002).
Linehan, S. A., Martinez-Pomares, L. & Gordon, S. Macrophage lectins in host defence. Microbes Infect. 2, 279–288 (2000).
de Fougerolles, A. R. et al. Global expression analysis of extracellular matrix–integrin interactions in monocytes. Immunity 13, 749–758 (2000).
Eggleton, P., Tenner, A. J. & Reid, K. M. M. C1q receptors. Clin. Exp. Immunol. 120, 406–412 (2000).
Brown, E. J. & Frazier, W. A. Integrin-associated protein (CD47) and its ligands. Trends Cell Biol. 11, 130–135 (2001).
Barclay, A. N., Wright, G. J., Brooke, G. & Brown, M. H. CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol. 213, 285–290 (2002).
Anderson, C. F. & Mosser, D. M. A novel phenotype for an activated macrophage: the type 2 activated macrophage. J. Leukocyte Biol. 72, 101–106 (2002).
Anderson, C. F. & Mosser, D. M. Cutting edge: biasing immune receptors by directing antigen to macrophage Fcγ receptors. J. Immunol. 168, 3697–3701 (2002).
Gerber, J. S. & Mosser, D. M. Reversing lipopolysaccharide toxicity by ligating the macrophage Fcγ receptors. J. Immunol. 166, 6861–6868 (2001).
Bach, E. A., Aguet, M. & Schreiber, R. D. The IFNγ receptor: a paradigm for cytokine receptor signalling. Annu. Rev. Immunol. 15, 563–591 (1997).
Nelms, K., Keegan, A. D., Zamorano, J., Ryan, J. J. & Paul, W. E. The IL-4 receptor: signalling mechanisms and biologic functions. Annu. Rev. Immunol. 17, 701–738 (1999).
Moore, K. W., de Waal Malefyt, R., Coffman, R. L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).
Tsunawaki, S., Sporn, M., Ding, A. & Nathan, C. Deactivation of macrophages by transforming growth factor-β. Nature 334, 260 (1988).
O'Garra, A. & Arai, N. The molecular basis of T helper 1 and T helper 2 cell differentiation. Trends Cell Biol. 10, 542–550 (2000).
Colonna, M. Can we apply the TH1–TH2 paradigm to all lymphocytes? Nature Immunol. 2, 899–900 (2001).
Monney, L. et al. TH1-specific cell-surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415, 536–541 (2002).
Chizzolini, C., Rezzonico, R., De Luca, C., Burger, D. & Dayer, J. -M. TH2 cell membrane factors in association with IL-4 enhance matrix metalloproteinase-1 (MMP-1) while decreasing MMP-9 production by granulocyte–macrophage colony-stimulating factor-differentiated human monocytes. J. Immunol. 164, 5952–5960 (2000).
Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).
Shortman, K. & Liu, Y. -J. Mouse and human dendritic-cell subtypes. Nature Immunol. 2, 151–161 (2002). An up-to-date assessment of dendritic-cell heterogeneity.
Takeda, K., Kamanaka, M., Tanaka, T., Kishimoto, T. & Akira, S. Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice. J. Immunol. 157, 3220–3222 (1996).
Shimoda, K. et al. Lack of IL-4 induced TH2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380, 630–633 (1996).
McKenzie, G. J. et al. Impaired development of TH2 cells in IL-13-deficient mice. Immunity 9, 423–432 (1998).
Kopf, M., Le, G. G., Coyle, A. J., Kosco, V. M. & Brombacher, F. Immune responses of IL-4, IL-5, IL-6 deficient mice. Immunol. Rev. 148, 45–69 (1995).
McKenzie, G. J., Fallon, P., Emson, C. L., Grencis, R. & McKenzie, A. N. J. Simultaneous disruption of interleukin (IL)-4 and IL-13 defines individual roles in T helper cell type-2-mediated responses. J. Exp. Med. 189, 1565–1572 (1999).
Mohrs, M. et al. Differences between IL-4- and IL-4 receptor-α-deficient mice in chronic Leishmaniasis reveal a protective role for IL-13 receptor signalling. J. Immunol. 162, 7302–7308 (1999).
Stein, M., Keshav, S., Harris, N. & Gordon, S. IL-4 potently enhances murine macrophage mannose receptor activity; a marker of alternative immunologic macrophage activation. J. Exp. Med. 176, 287–292 (1992). The first report of the upregulation of expression of macrophage mannose receptor by IL-4, and suggested use of the term 'alternative activation' to distinguish this mechanism from the previously reported downregulation of expression by IFN-γ.
McInnes, A. & Rennick, D. M. Interleukin-4 induces cultured monocytes/macrophages to form giant multinucleated cells. J. Exp. Med. 167, 598–611 (1988).
Mokoena, T. & Gordon, S. Activation of human macrophages. Modulation of mannosyl, fucosyl receptors for endocytosis by lymphokine, γ and α interferons and dexamethasone. J. Clin. Invest. 75, 624–631 (1985).
Doyle, A. G. et al. Interleukin-13 alters the activation state of murine macrophages in vitro: comparison with interleukin-4 and interferon-γ. Eur. J. Immunol. 24, 1441–1445 (1994).
Doherty, T. M., Kastelein, R., Menon, S., Andrade, S. & Coffman, R. L. Modulation of murine macrophage function by IL-13. J. Immunol. 151, 7151–7160 (1993).
de Waal Malefyt, R. et al. Effects of IL-13 on phenotype, cytokine production and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-γ or IL-10. J. Immunol. 151, 6370–6381 (1993).
Hart, P. H. et al. Differential responses of human monocytes and macrophages to IL-4 and IL-13. J. Leukoc. Biol. 66, 575–578 (1999).
Montaner, L. J. et al. Type-1 and type-2 cytokine regulation of macrophage endocytosis: differential activation by IL-4/IL-13 as opposed to IFN-γ or IL-10. J. Immunol. 162, 4606–4613 (1999).
Prigozy, T. I. et al. The mannose receptor delivers lipoglycan antigens to endosomes for presentation to T cells by CD1b molecules. Immunity 6, 187–197 (1997).
Sallusto, F., Cella, M., Danieli, C. & Lanzavecchia, A. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J. Exp. Med. 182, 389–400 (1995).
Martinez-Pomares, L. & Gordon, S. The mannose receptor and its role in antigen presentation. The Immunologist 7, 119–123 (1999).
Loke, P. et al. IL-4-dependent alternatively activated macrophages have a distinctive in vivo gene-expression phenotype. BMC Immunol. 3, 7 (2002).
Takemoto, N. et al. Cutting edge: chromatin remodelling at the IL-4/IL-13 intergenic regulatory region for TH2-specific cytokine gene cluster. J. Immunol. 165, 6687–6691 (2000).
Avni, O. et al. TH-cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nature Immunol. 3, 643–651 (2002).
Saccani, S., Pantano, S. & Natoli, G. Two waves of nuclear factor-κB recruitment to target promoters. J. Exp. Med. 193, 1351–1360 (2001).
Sallusto, F. & Lanzavecchia, A. Understanding dendritic-cell and T-lymphocyte traffic through the analysis of chemokine-receptor expression. Immunol. Rev. 177, 134–140 (2000).
Mantovani, A., Locati, M., Vecchi, A., Sozzani, S. & Allavena, P. Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines. Trends Immunol. 22, 328–336 (2001).
Fenton, M. J., Buras, J. A. & Donnelly, R. P. IL-4 reciprocally regulated IL-1 and IL-1 receptor antagonist expression in human monocytes. J. Immunol. 149, 1283–1288 (1992).
Bonecchi, R. et al. Divergent effects of interleukin-4 and interferon-γ on macrophage-derived chemokine production: an amplification circuit of polarized T helper 2 responses. Blood 92, 2668–2671 (1998). A description of a useful chemokine marker (macrophage-derived chemokine) that is consistent with the model of IL-4 versus IFN-γ regulation of macrophage activity, relating to T H 2-polarized responses, by a group that has made several important contributions to this field.
Andrew, D. P. et al. STCP-1 (MDC) CC-chemokine acts specifically on chronically activated TH2 lymphocytes and is produced by monocytes on stimulation with TH2 cytokines IL-4 and IL-13. J. Immunol. 161, 5027–5038 (1998).
Imai, T. et al. Selective recruitment of CCR4-bearing TH2 cells toward antigen-presenting cells by the CC-chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. Int. Immunol. 11, 81–88 (1999).
Bonecchi, R. et al. Induction of functional IL-8 receptors by IL-4 and IL-13 in human monocytes. J. Immunol. 164, 3862–3869 (2000).
Gordon, S. & Hughes, D. A. in Lung Macrophages and Dendritic Cells in Health & Disease (eds Lipscomb, M. & Russell, S.) 3–31 (Marcel Dekker, New York, 1997).
Zhu, Z. et al. IL-13-induced chemokine responses in the lung: role of CCR2 in the pathogenesis of IL-13-induced inflammation and remodelling. J. Immunol. 168, 2953–2962 (2002).
Traynor, T. R., Kuziel, W. A., Toews, G. B. & Huffnagle, G. B. CCR2 expression determines T1 versus T2 polarization during pulmonary Cryptococcus neoformans infection. J. Immunol. 164, 2021–2027 (2000).
Gu, L., Tseng, S., Horner, R. M., Tam, C., Loda, M. & Rollins, B. J. Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 404, 407–411 (2000).
Gao, J. -L. et al. Impaired host defense, hematopoiesis, granulomatous inflammation and type-1–type 2 cytokine balance in mice lacking CC-chemokine receptor 1. J. Exp. Med. 185, 1959–1968 (1997).
Medoff, B. D. et al. IFN-γ-inducible protein 10 (CXCL10) contributes to airway hyperreactivity and airway inflammation in a mouse model of asthma. J. Immunol. 168, 5278–5286 (2002).
Fort, M. M. et al. IL-25 induces IL-4, IL-5 and IL-13 and TH2-associated pathologies in vivo. Immunity 15, 985–995 (2001). A description of a new cytokine (IL-25) that induces the production of T H 2 cytokines and associated pathologies in the host.
Ruth, J. H. et al. Interleukin-4 and -13 participation in mycobacterial (type-1) and schistosomal (type-2) antigen-elicited pulmonary granuloma formation: multiparameter analysis of cellular recruitment, chemokine expression and cytokine networks. Cytokine 12, 432–444 (2000). This article explores the role of chemokine receptors in a schistosome granuloma model by groups who have made important contributions to the study of T H 2 immune-cell recruitment and pathology.
Chensue, S. W., Warmington, K., Ruth, J. H., Lukacs, N. & Kunkel, S. L. Mycobacterial and schistosomal antigen-elicited granuloma formation in IFN-γ and IL-4 knockout mice: analysis of local and regional cytokine and chemokine networks. J. Immunol. 159, 3565–3573 (1997).
Warmington, K. S. et al. Effect of CC-chemokine receptor 2 (CCR2) knockout on type-2 (schistosomal antigen-elicited) pulmonary granuloma formation: analysis of cellular recruitment and cytokine responses. Am. J. Pathol. 154, 1407–1416 (1999).
Jankovic, D. et al. Schistosome-infected IL-4 receptor knockout (KO) mice, in contrast to IL-4 KO mice, fail to develop granulomatous pathology while maintaining the same lymphokine expression profile. J. Immunol. 163, 337–342 (1999).
Rutschman, R. et al. Cutting edge: Stat6-dependent substrate depletion regulates nitric oxide production. J. Immunol. 166, 2173–2177 (2001).
Munder, M., Eichmann, K. & Modolell, M. 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 (1998).
Munder, M. et al. TH1/TH2-regulated expression of arginase isoforms in murine macrophages and dendritic cells. J. Immunol. 163, 3771–3777 (1999).
Hesse, M., Cheever, A. W., Jankovic, D. & Wynn, T. A. NOS-2 mediates the protective anti-inflammatory and antifibrotic effects of the TH1-inducing adjuvant, IL-12, in a TH2 model of granulomatous disease. Am. J. Pathol. 157, 945–955 (2000).
Hesse, M. et al. Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. J. Immunol. 167, 6533–6544 (2001). This paper describes the link between arginine metabolism and T H 2-cell activation, granuloma formation and repair.
Namangala, B., De Baetselier, P., Noel, W., Brys, L. & Beschin, A. Alternative versus classical macrophage activation during experimental African trypanosomosis. J. Leukocyte Biol. 69, 387–396 (2001).
Raes, G. et al. Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages. J. Leukocyte Biol. 71, 597–602 (2002).
Welch, J. S. et al. TH2 cytokines and allergic challenge induce Ym1 expression in macrophages by a STAT6-dependent mechanism. J. Biol. Chem. 277, 42821–42829 (2002).
Webb, D. C., McKenzie, A. N. & Foster, P. S. Expression of the Ym2 lectin-binding protein is dependent on interleukin (IL-4) and IL-13 signal transduction: identification of a novel allergy-associated protein. J. Biol. Chem. 276, 41969–41976 (2001).
Loke, P., MacDonald, A. S., Robb, A., Maizels, R. M. & Allen, J. E. Alternatively activated macrophages induced by nematode infection inhibit proliferation via cell-to-cell contact. Eur. J. Immunol. 30, 2669–2678 (2000).
Wegmann, T. G., Lin, H., Guilbert, L. & Mosmann, T. R. Bidirectional cytokine interactions in the maternal–fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol. Today 14, 353–356 (1993).
Dealtry, G. B., O'Farrell, M. K. & Fernandez, N. The TH2 cytokine environment of the placenta. Int. Arch. Allergy Immunol. 123, 107–119 (2000).
Mues, B., Langer, D., Zwadlo, G. & Sorg, C. Phenotypic characterization of macrophages in human term placenta. Immunology 67, 303–307 (1989).
Mellor, A. L. et al. Prevention of T-cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy. Nature Immunol. 2, 64–68 (2001).
Bonney, E. A. & Matzinger, P. Much IDO about pregnancy. Nature Med. 4, 1128–1129 (1998).
Kodelja, V. et al. Differences in angiogenic potential of classically vs alternatively activated macrophages. Immunobiology 197, 478–493 (1997).
Albina, J. E., Mills, C. D., Henry, W. L. Jr & Caldwell, M. D. Temporal expression of different pathways of L-arginine metabolism in healing wounds. J. Immunol. 144, 3877 (1990).
Andersson, P. -B., Perry, V. H. & Gordon, S. The acute inflammatory response to lipopolysaccharide in CNS parenchyma differs from that in other body tissues. Neuroscience 48, 169–186 (1992).
Glass, C. K. & Witztum, J. L. Atherosclerosis, the road ahead. Cell 104, 503–516 (2001). An overview of atherosclerosis as a modified form of inflammatory response, in which macrophages have an important role.
Gupta, S. et al. IFN-γ potentiated atherosclerosis in ApoE knock-out mice. J. Clin. Invest. 99, 2752–2761 (1997).
Greaves, D. R. et al. Linked chromosome 16q13 chemokines, macrophage-derived chemokine, fractalkine, and thymus- and activation-regulated chemokine, are expressed in human atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 21, 923–929 (2001).
Huang, J. T. et al. Interleukin-4-dependent production of PPAR-γ ligands in macrophages by 12/15-lipoxygenase. Nature 400, 378–382 (1999).
Balkwill, F. R. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).
Kapp, U. et al. Interleukin-13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells. J. Exp. Med. 189, 1939–1945 (1999).
van den Berg, A., Visser, L. & Poppema, S. High expression of the CC-chemokine TARC in Reed-Sternberg cells. A possible explanation for the characteristic T-cell infiltratein Hodgkin's lymphoma. Am. J. Pathol. 154, 1685–1691 (1999).
Schutyser, E. et al. Identification of biologically active chemokine isoforms from ascitic fluid and elevated levels of CCL18/pulmonary and activation-regulated chemokine in ovarian carcinoma. J. Biol. Chem. 277, 24584–24593 (2002).
Lin, E. Y., Nguyen, A. V., Russell, R. G. & Pollard, J. W. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 193, 727–740 (2001).
Nowicki, A. et al. Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of CSF-1-dependent macrophages in formation of tumor stroma. Int. J. Cancer 65, 112–119 (1996).
Crowther, M., Brown, N. J., Bishop, E. T. & Lewis, C. E. Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors. J. Leukocyte Biol. 70, 478–490 (2001).
Geldhof, A. B. et al. Antagonistic effect of NK cells on alternatively activated monocytes: a contribution of NK cells to CTL generation. Blood 100, 4049–4058 (2002).
Chiaramonte, M. G., Donaldson, D. D., Cheever, A. W. & Wynn, T. A. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J. Clin. Invest. 104, 777–785 (1999).
Stacey, M., Lin, H. -H., Gordon, S. & McKnight, A. J. LNB-TM7, a novel group of seven-transmembrane proteins related to family-B G-protein-coupled receptors. Trends Biochem. Sci. 25, 284–289 (2000).
Randolph, G. J. Dendritic-cell migration to lymph nodes: cytokines, chemokines and lipid mediators. Semin. Immunol. 13, 267–274 (2001).
Loots, G. G. et al. Identification of a co-ordinate regulator of interleukins 4, 13 and 5 by cross-species sequence comparisons. Science 288, 136–140 (2000).
Mohrs, M. et al. Deletion of a co-ordinate regulator of type-2 cytokine expression in mice. Nature Immunol. 2, 826–828 (2001).
Lee, G. R., Fields, P. E. & Flavell, R. A. Regulation of IL-4 gene expression by distal regulatory elements and GATA-3 at the chromatin level. Immunity 14, 447–459 (2001).
Fields, P. E., Kim, S. T. & Flavell, R. A. Cutting edge: changes in histone acetylation at the IL-4 and IFN-γ loci accompany TH1/TH2 differentiation. J. Immunol. 169, 647–650 (2002).
Fallon, P. G. et al. IL-4 induces characteristic TH2 responses even in the combined absence of IL-5, IL-9 and IL-13. Immunity 17, 7–17 (2002).
Brubaker, J. O. & Montaner, L. J. Role of interleukin-13 in innate and adaptive immunity. Cell. Mol. Biol. 47, 637–651 (2001).
Brombacher, F. The role of interleukin-13 in infectious diseases and allergy. BioEssays 22, 646–656 (2000). A comprehensive review of the production of IL-13 and its role in wild-type and gene-knockout animal models.
Donnelly, R. P., Dickensheets, H. & Finbloom, D. S. The interleukin-10 signal-transduction pathway and regulation of gene expression in mononuclear phagocytes. J. Interferon Cytokine Res. 19, 563–573 (1999).
Lang, R., Rutschman, R. L., Greaves, D. R. & Murray, P. J. Autocrine deactivation of macrophages in transgenic mice constitutively overexpressing IL-10 under control of the human CD68 promoter. J. Immunol. 168, 3402–3411 (2002).
Lang, R., Patel, D., Morris, J. J., Rutschman, R. L. & Murray, P. J. Shaping gene expression in activated and resting primary macrophages by IL-10. J. Immunol. 169, 2253–2263 (2002).
East, L. & Isacke, C. M. The mannose-receptor family. Biochem. Biophys. Acta. 1572, 364–386 (2002).
Lee, S. J. et al. Mannose receptor-mediated regulation of serum glycoprotein homeostasis. Science 295, 1898–1901 (2002).
Martinez-Pomares, L. et al. Cell-specific glycoforms of sialoadhesin and CD45 are counter receptors for the cysteine-rich domain of the mannose receptor. J. Biol. Chem. 274, 35211–35218 (1999).
Becker, S. & Daniel, E. G. Antagonistic and additive effects of IL-4 and IFN-γ on human monocytes and macrophages: effects on Fc receptors, HLA-D antigens and superoxide production. Cell. Immunol. 129, 351–362 (1990).
Kristiansen, M. et al. Identification of the haemoglobin scavenger receptor. Nature 409, 198–201 (2001).
Goerdt, S., Walsh, L. J., Murphy, G. F. & Pober, J. S. Identification of a novel high molecular weight protein preferentially expressed by sinusoidal endothelial cells in normal human tissues. J. Cell. Biol. 113, 1425–1437 (1991).
Gratchev, A. et al. Alternatively activated macrophages differentially express fibronectin and its splice variants and the extracellular matrix protein βIG-H3. Scand. J. Immunol. 53, 386–392 (2001).
Kodelja, V. et al. Alternative macrophage activation-associated CC-chemokine 1, a novel structural homologue of macrophage inflammatory protein-1α with a TH2-associated expression pattern. J. Immunol. 160, 1411–1418 (1998).
Kambayashi, T., Jacob, C. O. & Strassmann, G. IL-4 and IL-13 modulate IL-10 release in endotoxin-stimulated murine peritoneal mononuclear phagocytes. Cell. Immunol. 171, 153–158 (1996).
Lee, C. G. et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor-β1. J. Exp. Med. 194, 809–821 (2001).
Conrad, D. J., Kuhn, H., Mulkins, M., Highland, E. & Sigal, E. Specific inflammatory cytokines regulate the expression of human monocyte 15-lipoxygenase. Proc. Natl Acad. Sci. USA 89, 217–221 (1992).
Acknowledgements
Work in my laboratory is supported by the Medical Research Council, UK, The Wellcome Trust, the Arthritis Research Campaign and the British Heart Foundation. I thank C. Holt for invaluable help with the preparation of this manuscript, and many colleagues for helpful discussions.
Author information
Authors and Affiliations
Related links
Related links
DATABASES
LocusLink
Glossary
- CRE–LOX TECHNOLOGY
-
Cre is a site-specific recombinase that recognizes and binds specific sites known as loxP. Two loxP sites recombine in the presence of Cre, allowing DNA that is cloned between two such sites to be removed by Cre-mediated recombination.
- CHROMATIN IMMUNOPRECIPITATION
-
(ChIP). The use of antibodies specific for transcription factors to precipitate nucleic-acid sequences from chromatin for amplification.
- SUPPRESSION SUBTRACTIVE HYBRIDIZATION
-
A method to isolate unique messenger RNA sequences from paired sources, by subtracting common sequences, for complementary-DNA production.
Rights and permissions
About this article
Cite this article
Gordon, S. Alternative activation of macrophages. Nat Rev Immunol 3, 23–35 (2003). https://doi.org/10.1038/nri978
Issue Date:
DOI: https://doi.org/10.1038/nri978
