Imbalanced gp130-Dependent Signaling in Macrophages Alters Macrophage Colony-Stimulating Factor Responsiveness via Regulation of c-fms Expression
Open accessAbstract
The mechanisms by which interleukin-6 (IL-6) family cytokines, which utilize the common receptor signaling subunit gp130, influence monocyte/macrophage development remain unclear. Here we have utilized macrophages devoid of either gp130-dependent STAT1/3 (gp130(Delta STAT/Delta STAT)) or extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein (MAP) kinase (gp130(Y757F/Y757F)) activation to assess the individual contribution of each pathway to macrophage formation. While the inhibition by IL-6 of macrophage colony-stimulating factor (M-CSF)-induced colony formation observed in gp130(wt/wt) mice was abolished in gp130(Delta STAT/Delta STAT) mice, inhibition of macrophage colony formation was enhanced in gp130(Y757F/Y757F) mice. In gp130(Delta STAT/Delta STAT) bone marrow-derived macrophages (BMMs), both IL-6- and M-CSF-induced ERK1/2 tyrosine phosphorylation was enhanced. By contrast, tyrosine phosphorylation of ERK1/2 in response to M-CSF was reduced in gp130(Y757F/Y757F) BMMs, and the pattern of ERK1/2 activation in gp130 mutant BMMs correlated with their opposing responsiveness to M-CSF-induced proliferation. When compared to the level of expression in gp130(wt/wt) BMMs, c-fms expression was elevated in gp130(Delta STAT/Delta STAT) BMMs but reduced in gp130(Y757F/Y757F) BMMs. Finally, an ERK1/2 inhibitor suppressed M-CSF-induced BMM proliferation, and this result corresponded to a reduction in c-fms expression. Collectively, these results provide a functional and causal correlation between gp130-dependent ERK MAP kinase signaling and c-fms gene activation, a finding that provides a potential mechanism underlying the inhibition of M-CSF-dependent macrophage development by IL-6 family cytokines in mice.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Defective STAT3 activation enhances SHP-2-ERK-MAPK activation pathways, most likely through an impaired STAT3-mediated induction of SOCS3.
“Similarly, defective STAT3 activation enhances SHP-2–ERK–MAPK activation pathways, most likely through an impaired STAT3-mediated induction of suppressor of cytokine signaling 3 (SOCS3) (111, 112).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [112]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Tebbutt, N. C., Giraud, A. S., Inglese, M., Jenkins, B., Waring, P., Clay, F. J., Malki, S., Alderman, B. M., Grail, D., Hollande, F., et al. (2002) · Nature Medicine · doi:10.1038/nm763 · Cited by 474 · see citing works
Self-citationSchmitz, J., Weissenbach, M., Haan, S., Heinrich, P. C., & Schaper, F. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.17.12848 · Cited by 388 · see citing works
Yang, B.-S., Hauser, C. A., Henkel, G., Colman, M. S., Beveren, C. V., Stacey, K. J., Hume, D. A., Maki, R. A., & Ostrowski, M. C. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.2.538 · Cited by 333 · see citing works
Ernst, M., Inglese, M., Waring, P., Campbell, I. K., Bao, S., Clay, F. J., Alexander, W. S., Wicks, I. P., Tarlinton, D. M., Novak, U., et al. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.2.189 · Cited by 227 · see citing works
Self-citationBüscher, D., Hipskind, R. A., Krautwald, S., Reimann, T., & Baccarini, M. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.1.466 · Cited by 176 · see citing works
Kim, H., Hawley, T. S., Hawley, R. G., & Baumann, H. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.3.1525 · Cited by 119 · cited 1× · see citing works
“Conversely, the gp130 substitution mutation removes the phosphotyrosine residue that simultaneously provides a binding site for SHP2 and SOCS3, and therefore disrupts the capacity of SOCS3 to negatively regulate gp130-dependent signaling (35) and of SHP2 to dephosphorylate critical tyrosine residues in the gp130-JAK s…”
Background
Flagged first, then by citations
Research works printed but not linked: 3
- [16]16. Ikebuchi, K., G. G. Wong, S. C. Clark, J. N. Ihle, Y. Hirai, and M. Ogawa. 1987. Interleukin 6 enhancement of interleukin 3-dependent proliferation of multipotential hemopoietic progenitors. Proc. Natl. Acad. Sci. USA 84: 90359039.
- [26]26. Metcalf, D. 1997. Murine hematopoietic stem cells committed to macrophage/dendritic cell formation: stimulation by Flk2-ligand with enhancement by regulators using the gp130 receptor chain. Proc. Natl. Acad. Sci. USA 94: 11552-11556.
- [40]40. Wiktor-Jedrzejczak, W., A. Bartocci, A. W. Ferrante, Jr., A. Ahmed-Ansari, K. W. Sell, J. W. Pollard, and E. R. Stanley. 1990. Total absence of colonystimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc. Natl. Acad. Sci. USA 87: 4828-4832.
Cited by
Sorted by citations
The pro- and anti-inflammatory properties of the cytokine interleukin-6
Scheller, J., Chalaris, A., Schmidt-Arras, D., & Rose-John, S. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.01.034 · Cited by 3,212 · see citing works
IL-6 as a keystone cytokine in health and disease
Hunter, C. A., & Jones, S. A. (2015) · Nature Immunology · doi:10.1038/ni.3153 · Cited by 2,511 · see citing works
Cytokines in Inflammatory Disease
Kany, S., Vollrath, J. T., & Relja, B. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20236008 · Cited by 2,027 · see citing works
“In models with gp130 knockout mice, the ability of IL-6 to enhance macrophage-colony stimulating factor (M-CSF) receptor expression, thereby accelerating monocyte differentiation to macrophages, was linked to its gp130 MAP kinase pathway [39].”
BackgroundIL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453 · see citing works
“Similarly, defective STAT3 activation enhances SHP-2–ERK–MAPK activation pathways, most likely through an impaired STAT3-mediated induction of suppressor of cytokine signaling 3 (SOCS3) (111, 112).”
BackgroundDirecting Transition from Innate to Acquired Immunity: Defining a Role for IL-6
Jones, S. A. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.6.3463 · Cited by 771 · see citing works
“However, these studies also highlight that the differentiation pathway adopted may depend on the nature of the signal transmitted via gp130, since M-CSF receptor expression is inversely related to the quality of the gp130-mediated STAT3 signal (54).”
BackgroundPleiotropy and specificity: insights from the interleukin 6 family of cytokines
Murakami, M., Kamimura, D., & Hirano, T. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.027 · Cited by 533 · see citing works
IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation
McLoughlin, R. M., Jenkins, B. J., Grail, D., Williams, A. S., Fielding, C. A., Parker, C. R., Ernst, M., Topley, N., & Jones, S. A. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501794102 · Cited by 332 · see citing works
Self-citationErnst, M., Najdovska, M., Grail, D., Lundgren–May, T., Büchert, M., Tye, H., Matthews, V. B., Armes, J. E., Bhathal, P. S., Hughes, N. R., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34944 · Cited by 346 · see citing works
Self-citationJenkins, B. J., Grail, D., Nheu, T., Najdovska, M., Wang, B., Waring, P., Inglese, M., McLoughlin, R. M., Jones, S. A., Topley, N., et al. (2005) · Nature Medicine · doi:10.1038/nm1282 · Cited by 308 · see citing works
“We cleared protein lysates, prepared from MEFs or snap-frozen stomachs in ice-cold lysis buffe”
MethodSelf-citationReview: IL-6 Transsignaling: The In Vivo Consequences
Jones, S. A., Richards, P. J., Scheller, J., & Rose‐John, S. (2005) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2005.25.241 · Cited by 251 · see citing works
From cytokine to myokine: The emerging role of interleukin-6 in metabolic regulation
Pal, M., Febbraio, M. A., & Whitham, M. (2014) · Immunology & Cell Biology · doi:10.1038/icb.2014.16 · Cited by 258 · see citing works
IL-6 <i>Trans</i>-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3
Greenhill, C. J., Rose-John, S., Lissilaa, R., Ferlin, W., Ernst, M., Hertzog, P. J., Mansell, A., & Jenkins, B. J. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002971 · Cited by 264 · see citing works
“Bone marrow macrophages were generated from the flushed femurs of mice as described previously (31).”
Self-citationGlycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways
Sims, N. A., Jenkins, B. J., Quinn, J. M. W., Nakamura, A., Glatt, M., Gillespie, M. T., Ernst, M., & Martin, T. J. (2004) · Journal of Clinical Investigation · doi:10.1172/jci19872 · Cited by 192 · see citing works
Self-citationBreast Cancer-Derived Exosomes Alter Macrophage Polarization via gp130/STAT3 Signaling
Ham, S., Lima, L. G., Chai, E. Z. P., Muller, A., Lobb, R. J., Krumeich, S., Wen, S., Wiegmans, A. P., & Möller, A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00871 · Cited by 191 · see citing works
“In the context of macrophages, an imbalance of gp130 signaling has an impact on M2 macrophage polarization (50).”
BackgroundCosta, M. M., Maehr, T., Díaz‐Rosales, P., Secombes, C. J., & Wang, T. (2011) · Molecular Immunology · doi:10.1016/j.molimm.2011.05.027 · Cited by 171 · see citing works
Rébé, C., Végran, F., Berger, H., & Ghiringhelli, F. (2013) · JAK-STAT · doi:10.4161/jkst.23010 · Cited by 216 · see citing works
GP130 cytokines and bone remodelling in health and disease.
Sims, N., & Walsh, N. (2010) · BMB Reports · doi:10.5483/bmbrep.2010.43.8.513 · Cited by 133 · see citing works
STAT3, a master regulator of anti-tumor immune response
Rébé, C., & Ghiringhelli, F. (2019) · Cancers · doi:10.3390/cancers11091280 · Cited by 129 · see citing works
Jenkins, B. J., Roberts, A. W., Greenhill, C., Najdovska, M., Lundgren–May, T., Robb, L. G., Grail, D., & Ernst, M. (2006) · Blood · doi:10.1182/blood-2006-08-040352 · Cited by 90 · see citing works
“Protein extraction and immunoblot analysis Lysates were prepared from snap-frozen cell suspensions and tissues in ice-cold lysis buffer, following which they were subjected to immunoblot analyses with the indicated primary antibodies as previously described.(30) Proteins were visualized using either the enhanced chemi…”
MethodSelf-citationMolecular mechanisms involved in dendritic cell dysfunction in cancer
Tang, M., Diao, J., & Cattral, M. S. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2317-8 · Cited by 106 · see citing works
“This effect of IL-6 was linked to its ability to increase macrophage colony-stimulating factor receptor (Csf1r) expression levels [147].”
The threshold of gp130-dependent STAT3 signaling is critical for normal regulation of hematopoiesis
Jenkins, B. J., Roberts, A. W., Najdovska, M., Grail, D., & Ernst, M. (2005) · Blood · doi:10.1182/blood-2004-09-3751 · Cited by 85 · see citing works
“Protein extraction and immunoblot analysis Lysates were prepared from snap-frozen cell pellets and tissues in ice-cold lysis buffer.(30) Lysates were cleared of debris by centrifugation, separated on 10% polyacrylamide gels and then transferred to nitrocellulose membranes.”
MethodSelf-citationPrimed innate immunity leads to autoinflammatory disease in PSTPIP2-deficient cmo mice
Chiţu, V., Ferguson, P. J., de Bruijn, R., Schlueter, A. J., Ochoa, L. A., Waldschmidt, T. J., Yeung, Y.-G., & Stanley, E. R. (2009) · Blood · doi:10.1182/blood-2009-02-204925 · Cited by 86 · see citing works
An Interleukin-6 Receptor Antibody Suppresses Atherosclerosis in Atherogenic Mice
Akita, K., Isoda, K., Sato-Okabayashi, Y., Kadoguchi, T., Kitamura, K., Ohtomo, F., Shimada, K., & Daida, H. (2017) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2017.00084 · Cited by 68 · see citing works
IL‐6 and IL‐12 specifically regulate the expression of Rab5 and Rab7 via distinct signaling pathways
Bhattacharya, M., Ojha, N., Solanki, S., Mukhopadhyay, C., Madan, R., Patel, N., Krishnamurthy, G., Kumar, S., Basu, S., & Mukhopadhyay, A. (2006) · EMBO Journal · doi:10.1038/sj.emboj.7601170 · Cited by 65 · see citing works
“Interestingly, pre- vious studies have shown that IL-6 induces Ets and AP-1 transcription factors through the activation of ERK MAP kinase pathway (Jenkins et al, 2004); those are also present in the 50-flanking regulatory region of rab 5c. Similarly, IL-12- activated p38 MAP kinase is shown to…”
Rojo, R., Pridans, C., Langlais, D., & Hume, D. A. (2017) · Clinical Science · doi:10.1042/cs20170238 · Cited by 60 · see citing works
Targeting the STAT3 oncogenic pathway: Cancer immunotherapy and drug repurposing
Dong, Y., Chen, J., Chen, Y., & Liu, S. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115513 · Cited by 54 · see citing works
Sims, N. A. (2008) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.08.025 · Cited by 43 · see citing works
Horan, K. A., Watanabe, K.-I., Kong, A. M., Bailey, C. G., Rasko, J. E. J., Sasaki, T., & Mitchell, C. A. (2007) · Blood · doi:10.1182/blood-2007-02-073874 · Cited by 45 · see citing works
Kim, J., Kim, H., Kwon, S. B., Lee, S. Y., Chung, S., Jeong, D., & Min, B. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.09.220 · Cited by 47 · see citing works
“This event is initiated by an interaction between M-CSF and M-CSF receptor that is encoded by the c-fms gene and is expressed on the surface of the cells during development [35,36].”
BackgroundViral IL-6 Blocks Neutrophil Infiltration during Acute Inflammation1
Fielding, C., McLoughlin, R., Colmont, C. S., Kovaleva, M., Harris, D., Rose-John, S., Topley, N., & Jones, S. A. (2005) · Journal of Immunology · doi:10.4049/jimmunol.175.6.4024 · Cited by 39 · see citing works
“In this respect, genetic approaches involving knock-in mice that exhibit altered gp130-mediated signaling capacity have shown that the quality of the signal relayed via STAT1/3 and ERK1/2 effects the nature of the cellular response (34, 35).”
BackgroundOncostatin M Receptor-β Signaling Limits Monocytic Cell Recruitment in Acute Inflammation1
Hams, E., Colmont, C. S., Dioszeghy, V., Hammond, V., Fielding, C., Williams, A., Tanaka, M., Miyajima, A., Taylor, P., Topley, N., et al. (2008) · Journal of Immunology · doi:10.4049/jimmunol.181.3.2174 · Cited by 32 · see citing works
Sáinz, J., Pérez, E., Gómez-Lopera, S., López‐Fernández, E., Moratalla, L., Oyonarte, S., & Jurado, M. (2008) · Cytokine · doi:10.1016/j.cyto.2007.11.018 · Cited by 28 · see citing works
“fumigatus [24–43].”
BackgroundGeorgakis, M. K., Malik, R., Gill, D., Franceschini, N., Sudlow, C. L. M., & Dichgans, M. (2019) · medRxiv · doi:10.1101/19007682 · Cited by 36 · see citing works
Ling, H.-Y., Yang, Z. H., Wang, P., Sun, Y., Ju, S.-G., Li, J., & Fu, J. X. (2021) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2021.109779 · Cited by 33 · see citing works
Blood stem cell fate regulation by Delta-1-mediated rewiring of IL-6 paracrine signaling.
Csaszar, E., Wang, W.-J., Usenko, T., Qiao, W., Delaney, C., Bernstein, I., & Zandstra, P. (2014) · Blood · doi:10.1182/blood-2013-08-520445 · Cited by 29 · see citing works
The Role of gp130 Cytokines in Tuberculosis
Ritter, K., Rousseau, J., & Hölscher, C. (2020) · Cells · doi:10.3390/cells9122695 · Cited by 22 · see citing works
“Due to this abundant expression, IL-11 exerts pleiotropic effects such as the stimulation of hemopoiesis [102], thrombopoiesis [103] and the modulation of macrophage differentiation [104].”
BackgroundLPS hypersensitivity of gp130 mutant mice is independent of elevated haemopoietic TLR4 signaling
Greenhill, C., Gould, J. A., Ernst, M., Jarnicki, A., Hertzog, P. J., Mansell, A. S., & Jenkins, B. J. (2011) · Immunology and Cell Biology · doi:10.1038/icb.2011.56 · Cited by 15 · see citing works
Self-citationGersuk, G. M., Hiraoka, A., & Marr, K. A. (2005) · Journal of Immunological Methods · doi:10.1016/j.jim.2005.01.018 · Cited by 17 · see citing works
GATA2 decommissioning of enhancers: A mechanism to constrain inflammatory signaling
Jung, M. M., Tran, V. L., Xiong, Y., Johnson, K. D., Katsumura, K. R., Liu, P., & Bresnick, E. H. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116344 · Cited by 6 · see citing works
“70 IL-6 IL-6 promotes granulopoiesis in the mouse 71 and regulates macrophage colony-stimulating factor 72 to promote macrophage differentiation, 73 consistent with the attenuated monocytic differentiation upon Il6st enhancer deletion (Figures S5E and S5F).”
Ge, J., Chu, H., Xiao, Q., Hao, W.-D., Shang, J., Zhu, T., Sun, Z.-G., & Wei, X. (2021) · Environmental Pollution · doi:10.1016/j.envpol.2021.116452 · Cited by 3 · see citing works
Dowling, J., Tate, M. D., Rosli, S., Bourke, N. M., Bitto, N. J., Lauterbach, M., Cheung, S., Ve, T., Kobe, B., Golenbock, D., et al. (2019) · Journal of Immunology · doi:10.4049/jimmunol.1800501 · Cited by 2
“Formation of the Mal:MyD88 signaling complex triggers downstream signaling cascades, involving MAP kinases, activation of transcription factors such as NF-kB (via p65 phosphorylation), and the initiation of proinflammatory responses (10, 17).”
BackgroundBelcastro, E. (2016) · doi:10.70675/ff11aacdz46ffz4fc1z83e6z2d9faaae5e68
“Indeed, it is known that the redox status in the cells plays an important role in the cellular development, such as proliferation, differentiation and apoptosis [218, 346, 347].”
BackgroundNew Trends in Vascular Inflammation Research: From Biology to Therapy
Aikawa, M., Manabe, I., & Marx, N. (2019) · Frontiers Research Topics · doi:10.3389/978-2-88945-637-6
- Authors
- Jenkins, B. J., Grail, D., Inglese, M., Quilici, C., Bozinovski, S., Wong, P., & Ernst, M.
- Affiliations
- Ludwig Cancer Research (BE)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Corresponding author
- Jenkins, Brendan J.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2004-02-01
- Volume
- 24
- Issue
- 4
- Pages
- 1453-1463
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC344172
- OpenAlex
- W2136491733
- Cited by
- 43
- References
- 0
- Citations by year
- 2025: 1 · 2023: 1 · 2021: 2 · 2020: 2 · 2019: 5 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 1 · 2014: 1 · 2013: 3 · 2012: 1
- FWCI
- 1.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- Ludwig Institute for Cancer Research
- National Health and Medical Research Council
- National Medical Research Council
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- gp130, macrophage colony-stimulating factor, c-fms, interleukin-6 family cytokines, STAT1/3 signaling, macrophage development, bone marrow-derived macrophages, macrophage proliferation
- MeSH terms
- Animals, Cell Division, Cell Line, DNA-Binding Proteins, Gene Expression Regulation, Hematopoietic Stem Cells, Humans, Macrophages, Membrane Glycoproteins, Mutation, Transcriptional Activation, Trans-Activators, Antigens, CD, Interleukin-6, Macrophage Colony-Stimulating Factor, Genes, fms, Protein Tyrosine Phosphatases, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Intracellular Signaling Peptides and Proteins, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 11
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
