CoChat
Sign Up
Cited by 198Cellular transport and secretionImmune Response and InflammationAutophagy in Disease and Therapy

Subcompartments of the macrophage recycling endosome direct the differential secretion of IL-6 and TNFα

Open access
Manderson, Anthony P., Kay, Jason G., Hammond, Luke A., Brown, Darren L., Stow, Jennifer L.·2007·The Journal of Cell Biology
DOI 10.1083/jcb.200612131PMC PMC2064421
Open this paper in CoChat — free account

Abstract

Activated macrophages secrete an array of proinflammatory cytokines, including tumor necrosis factor-α (TNFα) and interleukin 6 (IL-6), that are temporally secreted for sequential roles in inflammation. We have previously characterized aspects of the intracellular trafficking of membrane-bound TNFα and its delivery to the cell surface at the site of phagocytic cups for secretion (Murray, R.Z., J.G. Kay, D.G. Sangermani, and J.L. Stow. 2005. Science. 310:1492–1495). The trafficking pathway and surface delivery of IL-6, a soluble cytokine, were studied here using approaches such as live cell imaging of fluorescently tagged IL-6 and immunoelectron microscopy. Newly synthesized IL-6 accumulates in the Golgi complex and exits in tubulovesicular carriers either as the sole labeled cargo or together with TNFα, utilizing specific soluble NSF attachment protein receptor (SNARE) proteins to fuse with the recycling endosome. Within recycling endosomes, we demonstrate the compartmentalization of cargo proteins, wherein IL-6 is dynamically segregated from TNFα and from surface recycling transferrin. Thereafter, these cytokines are independently secreted, with TNFα delivered to phagocytic cups but not IL-6. Therefore, the recycling endosome has a central role in orchestrating the differential secretion of cytokines during inflammation.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1083/jcb.200612131

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.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Upon stimulation of macrophages with LPS, IL-6 starts accumulating in the Golgi after 4 h of stimulation.

    “Upon stimulation of macrophages with LPS, IL-6 starts accumulating in the Golgi after 4 h of stimulation (45).”

    From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [45]

    The Results section, “Temporal secretion of IL-6 and TNFα in activated macrophages,” says IL-6 can be detected in the supernatant from 4 h after LPS stimulation, but its accumulation in the Golgi is not visible until 6 h. The claim conflates the 4-h secretion time with visible Golgi accumulation. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Knockdown and overexpression of these SNAREs decreases and augments IL-6 release, respectively.

    “Knockdown and overexpression of these SNAREs decreases and augments IL-6 release, respectively (45).”

    From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [45]

  • Three-dimensional reconstruction of fluorescence images showed that recycling endosomes can harbor both TNF and IL-6, albeit both occupy different subcompartments.

    “Three-dimensional reconstruction of fluorescence images showed that recycling endosomes can harbor both TNF and IL-6, albeit both occupy different subcompartments (45).”

    From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [45]

  • Unlike TNF, IL-6 is not secreted at the phagocytic cup.

    “Unlike TNF, IL-6 is not secreted at the phagocytic cup (45).”

    From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [45]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 60 · Cited by 198

Research works printed but not linked: 58

  1. Andersson, U., and T. Matsuda. 1989. Human interleukin 6 and tumor necrosis factor alpha production studied at a single-cell level. Eur. J. Immunol. 19: 1157–1160. 2526742
  2. Ang, A.L., T. Taguchi, S. Francis, H. Folsch, L.J. Murrells, M. Pypaert, G. Warren, and I. Mellman. 2004. Recycling endosomes can serve as intermediates during transport from the Golgi to the plasma membrane of MDCK cells. J. Cell Biol. 167: 531–543. 15534004 PMC2172492
  3. Arvan, P., B.Y. Zhang, L. Feng, M. Liu, and R. Kuliawat. 2002. Lumenal protein multimerization in the distal secretory pathway/secretory granules. Curr. Opin. Cell Biol. 14: 448–453. 12383795
  4. Bajno, L., X.R. Peng, A.D. Schreiber, H.P. Moore, W.S. Trimble, and S. Grinstein. 2000. Focal exocytosis of VAMP3-containing vesicles at sites of phagosome formation. J. Cell Biol. 149: 697–706. 10791982 PMC2174839
  5. Barton, B.E., and J.V. Jackson. 1993. Protective role of interleukin 6 in the lipopolysaccharide-galactosamine septic shock model. Infect. Immun. 61: 1496–1499. 8454355 PMC281391
  6. Beutler, B.A. 1999. The role of tumor necrosis factor in health and disease. J. Rheumatol. Suppl. 57: 16–21. 10328138
  7. Bonifacino, J.S., and R. Rojas. 2006. Retrograde transport from endosomes to the trans-Golgi network. Nat. Rev. Mol. Cell Biol. 7: 568–579. 16936697
  8. Braun, V., V. Fraisier, G. Raposo, I. Hurbain, J.B. Sibarita, P. Chavrier, T. Galli, and F. Niedergang. 2004. TI-VAMP/VAMP7 is required for optimal phagocytosis of opsonised particles in macrophages. EMBO J. 23: 4166–4176. 15470500 PMC524391
  9. Brown, D.L., K. Heimann, J. Lock, L. Kjer-Nielsen, C. van Vliet, J.L. Stow, and P.A. Gleeson. 2001. The GRIP domain is a specific targeting sequence for a population of trans-Golgi network derived tubulo-vesicular carriers. Traffic. 2: 336–344. 11350629
  10. Caplan, M.J., J.L. Stow, A.P. Newman, J. Madri, H.C. Anderson, M.G. Farquhar, G.E. Palade, and J.D. Jamieson. 1987. Dependence on pH of polarized sorting of secreted proteins. Nature. 329: 632–635. 2821405
  11. Casanova, J.E., X. Wang, R. Kumar, S.G. Bhartur, J. Navarre, J.E. Woodrum, Y. Altschuler, G.S. Ray, and J.R. Goldenring. 1999. Association of Rab25 and Rab11a with the apical recycling system of polarized Madin-Darby canine kidney cells. Mol. Biol. Cell. 10: 47–61. 9880326 PMC25153
  12. Clemens, D.L., and M.A. Horwitz. 1995. Characterization of the Mycobacterium tuberculosis phagosome and evidence that phagosomal maturation is inhibited. J. Exp. Med. 181: 257–270. 7807006 PMC2191842
  13. Collins, R.F., A.D. Schreiber, S. Grinstein, and W.S. Trimble. 2002. Syntaxins 13 and 7 function at distinct steps during phagocytosis. J. Immunol. 169: 3250–3256. 12218144
  14. Cox, D., D.J. Lee, B.M. Dale, J. Calafat, and S. Greenberg. 2000. A Rab11-containing rapidly recycling compartment in macrophages that promotes phagocytosis. Proc. Natl. Acad. Sci. USA. 97: 680–685. 10639139 PMC15390
  15. Daro, E., P. van der Sluijs, T. Galli, and I. Mellman. 1996. Rab4 and cellubrevin define different early endosome populations on the pathway of transferrin receptor recycling. Proc. Natl. Acad. Sci. USA. 93: 9559–9564. 8790369 PMC38467
  16. Ellis, M.A., B.A. Potter, K.O. Cresawn, and O.A. Weisz. 2006. Polarized biosynthetic traffic in renal epithelial cells: sorting, sorting, everywhere. Am. J. Physiol. Renal Physiol. 291: F707–F713. 16788143
  17. Futter, C.E., C.N. Connolly, D.F. Cutler, and C.R. Hopkins. 1995. Newly synthesized transferrin receptors can be detected in the endosome before they appear on the cell surface. J. Biol. Chem. 270: 10999–11003. 7738042
  18. Gagescu, R., N. Demaurex, R.G. Parton, W. Hunziker, L.A. Huber, and J. Gruenberg. 2000. The recycling endosome of Madin-Darby canine kidney cells is a mildly acidic compartment rich in raft components. Mol. Biol. Cell. 11: 2775–2791. 10930469 PMC14955
  19. Ghosh, P., N.M. Dahms, and S. Kornfeld. 2003. Mannose 6-phosphate receptors: new twists in the tale. Nat. Rev. Mol. Cell Biol. 4: 202–212. 12612639
  20. Heimann, K., J.M. Percival, R. Weinberger, P. Gunning, and J.L. Stow. 1999. Specific isoforms of actin-binding proteins on distinct populations of Golgi-derived vesicles. J. Biol. Chem. 274: 10743–10750. 10196146
  21. Hurst, S.M., T.S. Wilkinson, R.M. McLoughlin, S. Jones, S. Horiuchi, N. Yamamoto, S. Rose-John, G.M. Fuller, N. Topley, and S.A. Jones. 2001. Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity. 14: 705–714. 11420041
  22. Huse, M., B.F. Lillemeier, M.S. Kuhns, D.S. Chen, and M.M. Davis. 2006. T cells use two directionally distinct pathways for cytokine secretion. Nat. Immunol. 7: 247–255. 16444260
  23. Jin, M., and J.R. Goldenring. 2006. The Rab11-FIP1/RCP gene codes for multiple protein transcripts related to the plasma membrane recycling system. Biochim. Biophys. Acta. 1759: 281–295. 16920206
  24. Jones, S.A. 2005. Directing transition from innate to acquired immunity: defining a role for IL-6. J. Immunol. 175: 3463–3468. 16148087
  25. Kandere-Grzybowska, K., R. Letourneau, D. Kempuraj, J. Donelan, S. Poplawski, W. Boucher, A. Athanassiou, and T.C. Theoharides. 2003. IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells. J. Immunol. 171: 4830–4836. 14568962
  26. Kay, J.G., R.Z. Murray, J.K. Pagan, and J.L. Stow. 2006. Cytokine secretion via cholesterol-rich lipid raft-associated SNAREs at the phagocytic cup. J. Biol. Chem. 281: 11949–11954. 16513632
  27. Kim, T., J.H. Tao-Cheng, L.E. Eiden, and Y.P. Loh. 2001. Chromogranin A, an “on/off” switch controlling dense-core secretory granule biogenesis. Cell. 106: 499–509. 11525735
  28. Kishimoto, T., S. Akira, M. Narazaki, and T. Taga. 1995. Interleukin-6 family of cytokines and gp130. Blood. 86: 1243–1254. 7632928
  29. Kracht, M., and J. Saklatvala. 2002. Transcriptional and post-transcriptional control of gene expression in inflammation. Cytokine. 20: 91–106. 12453467
  30. Kwak, D.J., N.H. Augustine, W.G. Borges, J.L. Joyner, W.F. Green, and H.R. Hill. 2000. Intracellular and extracellular cytokine production by human mixed mononuclear cells in response to group B streptococci. Infect. Immun. 68: 320–327. 10603404 PMC97137
  31. Lapierre, L.A., and J.R. Goldenring. 2005. Interactions of myosin vb with rab11 family members and cargoes traversing the plasma membrane recycling system. Methods Enzymol. 403: 715–723. 16473633
  32. Lapierre, L.A., M.C. Dorn, C.F. Zimmerman, J. Navarre, J.O. Burnette, and J.R. Goldenring. 2003. Rab11b resides in a vesicular compartment distinct from Rab11a in parietal cells and other epithelial cells. Exp. Cell Res. 290: 322–331. 14567990
  33. Lock, J.G., and J.L. Stow. 2005. Rab11 in recycling endosomes regulates the sorting and basolateral transport of E-cadherin. Mol. Biol. Cell. 16: 1744–1755. 15689490 PMC1073657
  34. Lock, J.G., L.A. Hammond, F. Houghton, P.A. Gleeson, and J.L. Stow. 2005. E-cadherin transport from the trans-Golgi network in tubulovesicular carriers is selectively regulated by golgin-97. Traffic. 6: 1142–1156. 16262725
  35. Meyers, J.M., and R. Prekeris. 2002. Formation of mutually exclusive Rab11 complexes with members of the family of Rab11-interacting proteins regulates Rab11 endocytic targeting and function. J. Biol. Chem. 277: 49003–49010. 12376546
  36. Moqbel, R., and J.J. Coughlin. 2006. Differential secretion of cytokines. Sci. STKE. 10.1126/stke.3382006pe26. 16757734 · DOI
  37. Murray, R.Z., J.G. Kay, D.G. Sangermani, and J.L. Stow. 2005a. A role for the phagosome in cytokine secretion. Science. 310: 1492–1495. 16282525
  38. Murray, R.Z., F.G. Wylie, T. Khromykh, D.A. Hume, and J.L. Stow. 2005b. Syntaxin 6 and Vti1b form a novel SNARE complex, which is up-regulated in activated macrophages to facilitate exocytosis of tumor necrosis Factor-alpha. J. Biol. Chem. 280: 10478–10483. 15640147
  39. Orzech, E., S. Cohen, A. Weiss, and B. Aroeti. 2000. Interactions between the exocytic and endocytic pathways in polarized Madin-Darby canine kidney cells. J. Biol. Chem. 275: 15207–15219. 10809756
  40. Polishchuk, R.S., E.V. Polishchuk, P. Marra, S. Alberti, R. Buccione, A. Luini, and A.A. Mironov. 2000. Correlative light-electron microscopy reveals the tubular-saccular ultrastructure of carriers operating between Golgi apparatus and plasma membrane. J. Cell Biol. 148: 45–58. 10629217 PMC2156208
  41. Polishchuk, R.S., E. San Pietro, A. Di Pentima, S. Tete, and J.S. Bonifacino. 2006. Ultrastructure of long-range transport carriers moving from the trans Golgi network to peripheral endosomes. Traffic. 7: 1092–1103. 16787435
  42. Powelka, A.M., J. Sun, J. Li, M. Gao, L.M. Shaw, A. Sonnenberg, and V.W. Hsu. 2004. Stimulation-dependent recycling of integrin beta1 regulated by ARF6 and Rab11. Traffic. 5: 20–36. 14675422
  43. Rodriguez-Boulan, E., and A. Musch. 2005. Protein sorting in the Golgi complex: shifting paradigms. Biochim. Biophys. Acta. 1744: 455–464. 15927284
  44. Rodriguez-Boulan, E., G. Kreitzer, and A. Musch. 2005. Organization of vesicular trafficking in epithelia. Nat. Rev. Mol. Cell Biol. 6: 233–247. 15738988
  45. Sbalzarini, I.F., and P. Koumoutsakos. 2005. Feature point tracking and trajectory analysis for video imaging in cell biology. J. Struct. Biol. 151: 182–195. 16043363
  46. Schlierf, B., G.H. Fey, J. Hauber, G.M. Hocke, and O. Rosorius. 2000. Rab11b is essential for recycling of transferrin to the plasma membrane. Exp. Cell Res. 259: 257–265. 10942597
  47. Shurety, W., A. Merino-Trigo, D. Brown, D.A. Hume, and J.L. Stow. 2000. Localization and post-Golgi trafficking of tumor necrosis factor-alpha in macrophages. J. Interferon Cytokine Res. 20: 427–438. 10805378
  48. Siddiqui, M.A., and L.J. Scott. 2005. Infliximab: a review of its use in Crohn's disease and rheumatoid arthritis. Drugs. 65: 2179–2208. 16225377
  49. Slot, J.W., H.J. Geuze, S. Gigengack, G.E. Lienhard, and D.E. James. 1991. Immuno-localization of the insulin regulatable glucose transporter in brown adipose tissue of the rat. J. Cell Biol. 113: 123–135. 2007617 PMC2288909
  50. Sonnichsen, B., S. De Renzis, E. Nielsen, J. Rietdorf, and M. Zerial. 2000. Distinct membrane domains on endosomes in the recycling pathway visualized by multicolor imaging of Rab4, Rab5, and Rab11. J. Cell Biol. 149: 901–914. 10811830 PMC2174575
  51. Spencer, L.A., R.C. Melo, S.A. Perez, S.P. Bafford, A.M. Dvorak, and P.F. Weller. 2006. Cytokine receptor-mediated trafficking of preformed IL-4 in eosinophils identifies an innate immune mechanism of cytokine secretion. Proc. Natl. Acad. Sci. USA. 103: 3333–3338. 16492782 PMC1413889
  52. Teter, K., G. Chandy, B. Quinones, K. Pereyra, T. Machen, and H.P. Moore. 1998. Cellubrevin-targeted fluorescence uncovers heterogeneity in the recycling endosomes. J. Biol. Chem. 273: 19625–19633. 9677389
  53. Trowbridge, I.S., J.F. Collawn, and C.R. Hopkins. 1993. Signal-dependent membrane protein trafficking in the endocytic pathway. Annu. Rev. Cell Biol. 9: 129–161. 8280459
  54. Ulich, T.R., S. Yin, K. Guo, E.S. Yi, D. Remick, and J. del Castillo. 1991. Intratracheal injection of endotoxin and cytokines. II. Interleukin-6 and transforming growth factor beta inhibit acute inflammation. Am. J. Pathol. 138: 1097–1101. 2024703 PMC1886022
  55. Ullrich, O., S. Reinsch, S. Urbe, M. Zerial, and R.G. Parton. 1996. Rab11 regulates recycling through the pericentriolar recycling endosome. J. Cell Biol. 135: 913–924. 8922376 PMC2133374
  56. van Ijzendoorn, S.C. 2006. Recycling endosomes. J. Cell Sci. 119: 1679–1681. 16636069
  57. Wylie, F., K. Heimann, T.L. Le, D. Brown, G. Rabnott, and J.L. Stow. 1999. GAIP, a Galphai-3-binding protein, is associated with Golgi-derived vesicles and protein trafficking. Am. J. Physiol. 276: C497–C506. 9950778
  58. Yeaman, C., K.K. Grindstaff, and W.J. Nelson. 2004. Mechanism of recruiting Sec6/8 (exocyst) complex to the apical junctional complex during polarization of epithelial cells. J. Cell Sci. 117: 559–570. 14709721 PMC3368615

Authors
Manderson, A. P., Kay, J. G., Hammond, L. A., Brown, D. L., & Stow, J. L.
Affiliations
The University of Queensland (AU)
ORCID
Venue
The Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2007-07-02
Volume
178
Issue
1
Pages
57-69
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.200612131
PMC
PMC2064421
OpenAlex
W2171599719
Cited by
198
References
60
Citations by year
2026: 3 · 2025: 12 · 2024: 10 · 2023: 13 · 2022: 8 · 2021: 11 · 2020: 13 · 2019: 10 · 2018: 15 · 2017: 9 · 2016: 9 · 2015: 11 · 2014: 9 · 2013: 11 · 2012: 8
FWCI
4.69
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Cell Biology (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
macrophages, recycling endosomes, interleukin-6, TNF-α, cytokine production, Golgi apparatus, SNARE proteins, membrane trafficking, phagocytic cup, transferrin recycling
MeSH terms
Cyclic AMP, Animals, Cell Line, Fluorescent Dyes, Macrophages, Microscopy, Fluorescence, Endosomes, Rhodamines, Transfection, Tumor Necrosis Factor-alpha, Interleukin-6, DNA, Complementary, Electroporation, Fluorescent Antibody Technique, Indirect, RNA, Small Interfering, Mice

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