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Cited by 1,960Immune cells in cancerPhagocytosis and Immune RegulationImmune Response and Inflammation

Interleukin 4 potently enhances murine macrophage mannose receptor activity: A marker of alternative immunologic macrophage activation

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Stein, M, Keshav, S, Harris, N, Gordon, S·1992·The Journal of experimental medicine
DOI 10.1084/jem.176.1.287PMC PMC2119288
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Abstract

Expression of the macrophage mannose receptor is inhibited by interferon gamma (IFN-gamma), a T helper type 1 (Th-1)-derived lymphokine. Interleukin 4 (IL-4), a Th-2 lymphocyte product, upregulates major histocompatibility class II antigen expression but inhibits inflammatory cytokine production by macrophages. We have studied the effect of IL-4 on expression of the macrophage mannose receptor (MMR) by elicited peritoneal macrophages. We found that recombinant murine IL-4 enhances MMR surface expression (10-fold) and activity (15-fold), as measured by the respective binding and degradation of 125I-mannose-bovine serum albumin. Polymerase chain reaction analysis of cDNAs from purified primary macrophage populations revealed that MMR, but not lysozyme or tumor necrosis factor alpha, mRNA levels were markedly increased by IL-4. The above effects were associated with morphologic changes. These data establish IL-4 as a potent and selective enhancer of murine MMR activity in vitro. IL-4 induces inflammatory macrophages to adopt an alternative activation phenotype, distinct from that induced by IFN-gamma, characterized by a high capacity for endocytic clearance of mannosylated ligands, enhanced (albeit restricted) MHC class II antigen expression, and reduced proinflammatory cytokine secretion.

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Crossref · 10.1084/jem.176.1.287

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  • Alternatively activated macrophages are stimulated by IL-4, IL-13 and glucocorticoids, inhibit pro-inflammatory cytokines, promote anti-inflammatory cytokines, and upregulate mannose receptors.

    “Alternatively activated macrophages are stimulated by IL-4, IL-13 and glucocorticoids, inhibit pro-inflammatory cytokines, promote anti-inflammatory cytokines, and upregulate mannose receptors.[123, 124]”

    From Foreign body reaction to biomaterials (2008) · cites this paper as [123]

    The Summary (p. 287) reports that IL-4 induces an alternative activation phenotype in murine macrophages, increases mannose receptor expression, and reduces pro-inflammatory cytokine secretion. The Introduction discusses steroids and their interaction with IL-4, but our copy does not establish the claimed role of glucocorticoids in stimulating alternative activation; it also does not address IL-13 or increased anti-inflammatory cytokine production. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Later, macrophages transit from M1 to reparative M2 phenotype, expressing anti-inflammatory mediators and growth factors, promoting fibroblast proliferation, ECM synthesis and angiogenesis.

    “Later during the healing process, macrophages transit from a pro-inflammatory M1 to a reparative M2 phenotype, expressing anti-inflammatory mediators, e.g., IL-1R antagonist, decoy IL-1 receptor type II and IL-10, and growth factors, e.g., TGFβ, VEGF and IGF1, promoting fibroblast proliferation, ECM synthesis and angiogenesis (Fig. 2) [59, 60].”

    From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [60]

    The Summary (p. 287) says IL-4 induces inflammatory murine macrophages to adopt an alternative activation phenotype with reduced proinflammatory cytokine secretion. It does not establish a transition during wound healing or report the listed anti-inflammatory mediators and growth factors, fibroblast proliferation, ECM synthesis, or angiogenesis. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • A phenotypic switch in biomaterial adherent macrophages to a more alternatively activated phenotype over time is expected because IL-4 is added to the culture system on days 3 and 7 to induce fusion, and IL-4 induces alternative activation including mannose receptor upregulation necessary for foreign body giant cell formation.

    “A phenotypic switch in biomaterial adherent macrophages to a more alternatively activated macrophage phenotype over time is expected because in order to induce fusion IL-4 is added to our culture system on days 3 and 7[58] IL-4 is known to induce an alternative activation phenotype in macrophages inclusive of the upregulation of mannose receptors[123] which has been found to be necessary for the”

    From Foreign body reaction to biomaterials (2008) · cites this paper as [123]

  • Alternatively activated macrophages do not require priming because IL-4 and/or IL-13 can act as sufficient stimuli.

    “Alternatively activated macrophages do not require any priming, because interleukins IL-4 and/or IL-13 can act as enough stimuli [190,191].”

    From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [190]

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Authors
Stein, M., Keshav, S., Harris, N., & Gordon, S.
Affiliations
University of Oxford (GB)
ORCID
Venue
The Journal of experimental medicine
Publisher
Rockefeller University Press
Published
1992-07-01
Volume
176
Issue
1
Pages
287-292
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.176.1.287
PMC
PMC2119288
OpenAlex
W2123640179
Cited by
1,960
References
21
Citations by year
2026: 48 · 2025: 66 · 2024: 74 · 2023: 80 · 2022: 115 · 2021: 102 · 2020: 92 · 2019: 93 · 2018: 94 · 2017: 106 · 2016: 116 · 2015: 110 · 2014: 137 · 2013: 100 · 2012: 88
FWCI
2.90
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
IL-4, CD206, alternative macrophage activation, interferon-gamma, peritoneal macrophages, mannose binding, MHC class II antigen expression, proinflammatory cytokine secretion
MeSH terms
Mannose Receptor, Animals, Base Sequence, Interferon-gamma, Macrophage Activation, Macrophages, Male, Mannose, Mice, Inbred BALB C, Molecular Sequence Data, Receptors, Cell Surface, Receptors, Immunologic, RNA, Messenger, Interleukin-4, Lectins, C-Type, Mannose-Binding Lectins, Mice

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