CoChat
Sign Up
Cited by 79Macrophage Migration Inhibitory FactorParasitic Diseases Research and TreatmentParasites and Host Interactions

MIF homologues from a filarial nematode parasite synergize with IL-4 to induce alternative activation of host macrophages

Open access
Prieto-Lafuente, Lidia, Gregory, William F, Allen, Judith E, Maizels, Rick M·2009·Journal of Leukocyte Biology
DOI 10.1189/jlb.0808459PMC PMC2691607
Open this paper in CoChat — free accountOpen PDF

Abstract

Macrophage migration inhibitory factor (MIF) is a highly conserved cytokine considered to exert wide-ranging, proinflammatory effects on the immune system. Recently, members of this gene family have been discovered in a number of invertebrate species, including parasitic helminths. However, chronic helminth infections are typically associated with a Th2-dominated, counter-inflammatory phenotype, in which alternatively activated macrophages (AAMs) are prominent. To resolve this apparent paradox, we have analyzed the activity of two helminth MIF homologues from the filarial nematode Brugia malayi, in comparison with the canonical MIF from the mouse. We report that murine MIF (mMIF) and Brugia MIF proteins induce broadly similar effects on bone marrow-derived mouse macrophages, eliciting a measured release of proinflammatory cytokines. In parallel, MIF was found to induce up-regulation of IL-4R on macrophages, which when treated in vitro with MIF in combination with IL-4, expressed markers of alternative activation [arginase, resistin-like molecule α (RELM-α) or found in inflammatory zone 1, Ym-1, murine macrophage mannose receptor] and differentiated into functional AAMs with in vitro-suppressive ability. Consistent with this finding, repeated in vivo administration of Brugia MIF induced expression of alternative macrophage activation markers. As mMIF did not induce RELM-α or Ym-1 in vivo, alternative activation may require components of the adaptive immune response to Brugia MIF, such as the production of IL-4. Hence, MIF may accentuate macrophage activation according to the polarity of the environment, thus promoting AAM differentiation in the presence of IL-4-inducing parasitic helminths.

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 · 10.1189/jlb.0808459

Cites

1 of 1 references verified0 citation errors · 0 not checkable

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?

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

Flagged first, then by citations

Research works printed but not linked: 71

  1. Bloom B R Bennett B Mechanism of a reaction in vitro associated with delayed-type hypersensitivity Science 153 1966 80 82 5938421
  2. David J R Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction Proc Natl Acad Sci USA 56 1966 72 77 5229858 PMC285677
  3. Bacher M Metz C N Calandra T Mayer K Chesney J Lohoff M Gemsa D Donnelly T Bucala R An essential regulatory role for macrophage migration inhibitory factor in T-cell activation Proc Natl Acad Sci USA 93 1996 7849 7854 8755565 PMC38837
  4. Calandra T Roger T Macrophage migration inhibitory factor: a regulator of innate immunity Nat Rev Immunol 3 2003 791 800 14502271 PMC7097468
  5. Calandra T Bernhagen J Mitchell R A Bucala R The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor J Exp Med 179 1994 1895 1902 8195715 PMC2191507
  6. Rossi A G Haslett C Hirani N Greening A P Rahman I Metz C N Bucala R Donnelly S C Human circulating eosinophils secrete macrophage migration inhibitory factor (MIF). Potential role in asthma J Clin Invest 101 1998 2869 2874 9637721 PMC508878
  7. Bernhagen J Calandra T Mitchell R A Martin S B Tracey K J Voelter W Manogue K R Cerami A Bucala R MIF is a pituitary-derived cytokine that potentiates lethal endotoxemia Nature 365 1993 756 759 8413654
  8. Metz C N Bucala R Role of macrophage migration inhibitory factor in the regulation of the immune response Adv Immunol 66 1997 197 223 9328642
  9. Lue H Kleemann R Calandra T Roger T Bernhagen J Macrophage migration inhibitory factor (MIF): mechanisms of action and role in disease Microbes Infect 4 2002 449 460 11932196
  10. Bozza M Satoskar A R Lin G Lu B Humbles A A Gerard C David J R Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis J Exp Med 189 1999 341 346 9892616 PMC2192995
  11. de Jong Y P Abadia-Molina A C Satoskar A R Clarke K Rietdijk S T Faubion W A Mizoguchi E Metz C N Alsahli M ten Hove T Keates A C Lubetsky J B Farrell R J Michetti P van Deventer S J Lolis E David J R Bhan A K Terhorst C Sahi M A Development of chronic colitis is dependent on the cytokine MIF Nat Immunol 2 2001 1061 1066 11668338
  12. Wang B Huang X Wolters P J Sun J Kitamoto S Yang M Riese R Leng L Chapman H A Finn P W David J R Bucala R Shi G-P Deficiency of macrophage migration inhibitory factor impairs murine airway allergic responses J Immunol 177 2006 5779 5784 17056501
  13. Magalhàes E S Mourao-Sa D S Vieira-de-Abreu A Figueiredo R T Pires A L Farias-Filho F A Fonseca B P F Viola J P B Metz C Martins M A Castro-Faria-Neto H C Bozza P T Bozza M T Macrophage migration inhibitory factor is essential for allergic asthma but not for Th2 differentiation Eur J Immunol 37 2007 1097 1106 17373669
  14. Roger T David J Glauser M P Calandra T MIF regulates innate immune responses through modulation of Toll-like receptor 4 Nature 414 2001 920 924 11780066
  15. Koebernick H Grode L David J R Rohde W Rolph M S Mittrucker H W Kaufmann S H Macrophage migration inhibitory factor (MIF) plays a pivotal role in immunity against Salmonella typhimurium Proc Natl Acad Sci USA 99 2002 13681 13686 12271144 PMC129741
  16. Satoskar A R Bozza M Rodriguez Sosa M Lin G David J R Migration-inhibitory factor gene-deficient mice are susceptible to cutaneous Leishmania major infection Infect Immun 69 2001 906 911 11159984 PMC97968
  17. Rodriguez-Sosa M Rosas L E David J R Bojalil R Satoskar A R Terrazas L I Macrophage migration inhibitory factor plays a critical role in mediating protection against the helminth parasite Taenia crassiceps Infect Immun 71 2003 1247 1254 12595439 PMC148860
  18. Rodríguez-Sosa M Saavedra R Tenorio E P Rosas L E Satoskar A R Terrazas L I A STAT4-dependent Th1 response is required for resistance to the helminth parasite Taenia crassiceps Infect Immun 72 2004 4552 4560 15271915 PMC470677
  19. Mitchell R A Mechanisms and effectors of MIF-dependent promotion of tumorigenesis Cell Signal 16 2004 13 19 14607271
  20. Apte R S Sinha D Mayhew E Wistow G J Niederkorn J Y Role of macrophage migration inhibitory factor in inhibiting NK cell activity and preserving immune privilege J Immunol 160 1998 5693 5696 9637476
  21. Repp A C Mayhew E S Apte S Niederkorn J Y Human uveal melanoma cells produce macrophage migration-inhibitory factor to prevent lysis by NK cells J Immunol 165 2000 710 715 10878343
  22. Yan X Orentas R J Johnson B D Tumor-derived macrophage migration inhibitory factor (MIF) inhibits T lymphocyte activation Cytokine 33 2006 188 198 16522371 PMC2018658
  23. Krockenberger M Dombrowski Y Weidler C Ossadnik M Honig A Hausler S Voigt H Becker J C Leng L Steinle A Weller M Bucala R Dietl J Wischhusen J Macrophage migration inhibitory factor contributes to the immune escape of ovarian cancer by down-regulating NKG2D J Immunol 180 2008 7338 7348 18490733 PMC3607742
  24. Zhou Q Yan X Gershan J Orentas R J Johnson B D Expression of macrophage migration inhibitory factor by neuroblastoma leads to the inhibition of antitumor T cell reactivity in vivo J Immunol 181 2008 1877 1886 18641325 PMC3804024
  25. Swope M Sun H-W Blake P Lolis E Direct link between cytokine activity and a catalytic site for macrophage migration inhibitory factor EMBO J 17 1998 3534 3541 9649424 PMC1170690
  26. Flieger O Engling A Bucala R Lue H Nickel W Bernhagen J Regulated secretion of macrophage migration inhibitory factor is mediated by a non-classical pathway involving an ABC transporter FEBS Lett 551 2003 78 86 12965208
  27. Rosengren E Bucala R Aman P Jacobsson L Odh G Metz C N Rorsman H The immunoregulatory mediator macrophage migration inhibitory factor (MIF) catalyzes a tautomerization reaction Mol Med 2 1996 143 149 8900542 PMC2230029
  28. Kleemann R Kapurniotu A Frank R W Gessner A Mischke R Flieger O Juttner S Brunner H Bernhagen J Disulfide analysis reveals a role for macrophage migration inhibitory factor (MIF) as thiol-protein oxidoreductase J Mol Biol 280 1998 85 102 9653033
  29. Bucala R MIF rediscovered: cytokine, pituitary hormone, and glucocorticoid-induced regulator of the immune response FASEB J 10 1996 1607 1613 9002552
  30. Bucala R A most interesting factor Nature 408 2000 146 147 11089953
  31. Leng L Metz C N Fang Y Xu J Donnelly S Baugh J Delohery T Chen Y Mitchell R A Bucala R MIF signal transduction initiated by binding to CD74 J Exp Med 197 2003 1467 1476 12782713 PMC2193907
  32. Lue H Kapurniotu A Fingerle-Rowson G Roger T Leng L Thiele M Calandra T Bucala R Bernhagen J Rapid and transient activation of the ERK MAPK signaling pathway by macrophage migration inhibitory factor (MIF) and dependence on JAB1/CSN5 and Src kinase activity Cell Signal 18 2005 688 703 16122907
  33. Shi X Leng L Wang T Wang W Du X Li J McDonald C Chen Z Murphy J W Lolis E Noble P Knudson W Bucala R CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex Immunity 25 2006 595 606 17045821 PMC3707630
  34. Bernhagen J Krohn R Lue H Gregory J L Zernecke A Koenen R R Dewor M Georgiev I Schober A Leng L Kooistra T Fingerle-Rowson G Ghezzi P Kleemann R McColl S R Bucala R Hickey M J Weber C MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment Nat Med 13 2007 587 596 17435771
  35. Kleemann R Hausser A Geiger G Mischke R Burger-Kentischer A Flieger O Johannes F J Roger T Calandra T Kapurniotu A Grell M Ginkelmeier D Brunner H Bernhagen J Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1 Nature 408 2000 211 216 11089976
  36. Maizels R M Balic A Gomez-Escobar N Nair M Taylor M Allen J E Helminth parasites: masters of regulation Immunol Rev 201 2004 89 116 15361235
  37. Vermeire J J Cho Y Lolis E Bucala R Cappello M Orthologs of macrophage migration inhibitory factor from parasitic nematodes Trends Parasitol 24 2008 355 363 18603473 PMC3615561
  38. Pastrana D V Raghavan N FitzGerald P Eisinger S W Metz C Bucala R Schleimer R P Bickel C Scott A L Filarial nematode parasites secrete a homologue of the human cytokine macrophage migration inhibitory factor Infect Immun 66 1998 5955 5963 9826378 PMC108754
  39. Zang X Taylor P Meyer D Wang J M Scott A L Walkinshaw M D Maizels R M Homologues of human macrophage migration inhibitory factor from a parasitic nematode: gene cloning, protein activity and crystal structure J Biol Chem 277 2002 44261 44267 12221083
  40. Cho Y Jones B F Vermeire J J Leng L DiFedele L Harrison L M Xiong H Kwong Y K Chen Y Bucala R Lolis E Cappello M Structural and functional characterization of a secreted hookworm macrophage migration inhibitory factor (MIF) that interacts with the human MIF receptor CD74 J Biol Chem 282 2007 23447 23456 17567581 PMC3707627
  41. Allen J E Loke P Divergent roles for macrophages in lymphatic filariasis Parasite Immunol 23 2001 345 352 11472554
  42. Linehan S A Coulson P S Wilson R A Mountford A P Brombacher F Martinez-Pomares L Gordon S IL-4 receptor signaling is required for mannose receptor expression by macrophages recruited to granulomata but not resident cells in mice infected with Schistosoma mansoni Lab Invest 83 2003 1223 1231 12920251
  43. Herbert D R Hölscher C Mohrs M Arendse B Schwegmann A Radwanska M Leeto M Kirsch R Hall P Mossmann H Claussen B Förster I Brombacher F Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology Immunity 20 2004 623 635 15142530
  44. Kreider T Anthony R M Urban J F Jr Gause W C Alternatively activated macrophages in helminth infections Curr Opin Immunol 19 2007 448 453 17702561 PMC2000338
  45. Falcone F H Loke P Zang X MacDonald A S Maizels R M Allen J E A Brugia malayi homolog of macrophage migration inhibitory factor reveals an important link between macrophages and eosinophil recruitment during nematode infection J Immunol 167 2001 5348 5354 11673551
  46. Loke P Nair M Parkinson J Guiliano D Blaxter M Allen J IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype BMC Immunol 3 2002 7 12098359 PMC117781
  47. Nair M G Cochrane D W Allen J E Macrophages in chronic type 2 inflammation have a novel phenotype characterized by the abundant expression of Ym1 and Fizz1 that can be partly replicated in vitro Immunol Lett 85 2003 173 180 12527225
  48. Nair M G Gallagher I J Taylor M D Loke P Coulson P S Wilson R A Maizels R M Allen J E Chitinase and Fizz family members are a generalized feature of nematode infection with selective upregulation of Ym1 and Fizz1 by antigen-presenting cells Infect Immun 73 2005 385 394 15618176 PMC538942
  49. Taylor P R Martinez-Pomares L Stacey M Lin H H Brown G D Gordon S Macrophage receptors and immune recognition Annu Rev Immunol 23 2005 901 944 15771589
  50. Allen J E Lawrence R A Maizels R M Antigen presenting cells from mice harboring the filarial nematode, Brugia malayi, prevent cellular proliferaton but not cytokine production Int Immunol 8 1996 143 151 8671598
  51. MacDonald A S Maizels R M Lawrence R A Dransfield I Allen J E Requirement for in vivo production of IL-4, but not IL-10, in the induction of proliferative suppression by filarial parasites J Immunol 160 1998 4124 4132 9558124
  52. 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 2000 2669 2678 11009101
  53. Owhashi M Arita H Hayai N Identification of a novel eosinophil chemotactic cytokine (ECF-L) as a chitinase family protein J Biol Chem 275 2000 1279 1286 10625674
  54. Voehringer D van Rooijen N Locksley R M Eosinophils develop in distinct stages and are recruited to peripheral sites by alternatively activated macrophages J Leukoc Biol 81 2007 1434 1444 17339609
  55. Weinstock J V Summers R Elliott D E Helminths and harmony Gut 53 2004 7 9 14684567 PMC1773927
  56. Else K J Have gastrointestinal nematodes outwitted the immune system? Parasite Immunol 27 2005 407 415 16179034
  57. Gordon S Alternative activation of macrophages Nat Rev Immunol 3 2003 23 35 12511873
  58. Hesse M Modolell M La Flamme A C Schito M Fuentes J M Cheever A W Pearce E J Wynn T A 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 2001 6533 6544 11714822
  59. Raes G De Baetselier P Noel W Beschin A Brombacher F Hassanzadeh Gh G Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages J Leukoc Biol 71 2002 597 602 11927645
  60. Rodríguez-Sosa M Satoskar A R Calderón R Gomez-Garcia L Saavedra R Bojalil R Terrazas L I Chronic helminth infection induces alternatively activated macrophages expressing high levels of CCR5 with low interleukin-12 production and Th2-biasing ability Infect Immun 70 2002 3656 3664 12065507 PMC128095
  61. Donnelly S O'Neill S M Sekiya M Mulcahy G Dalton J P Thioredoxin peroxidase secreted by Fasciola hepatica induces the alternative activation of macrophages Infect Immun 73 2005 166 173 15618151 PMC538930
  62. Guo L Johnson R S Schuh J C L Biochemical characterization of endogenously formed eosinophilic crystals in the lungs of mice J Biol Chem 275 2000 8032 8037 10713123
  63. Marson A L Tarr D E K Scott A L Macrophage migration inhibitory factor (MIF) transcription is significantly elevated in Caenorhabditis elegans dauer larvae Gene 278 2001 53 62 11707322
  64. Sato A Uinuk-ool T S Kuroda N Mayer W E Takezaki N Dongak R Figueroa F Cooper M D Klein J Macrophage migration inhibitory factor (MIF) of jawed and jawless fishes: implications for its evolutionary origin Dev Comp Immunol 27 2003 401 412 12631522
  65. Augustijn K D Kleemann R Thompson J Kooistra T Crawford C E Reece S E Pain A Siebum A H G Janse C J Waters A P Functional characterization of the Plasmodium falciparum and P. berghei homologues of macrophage migration inhibitory factor Infect Immun 75 2007 1116 1128 17158894 PMC1828592
  66. Cordery D V Kishore U Kyes S Shafi M J Watkins K R Williams T N Marsh K Urban B C Characterization of a Plasmodium falciparum macrophage-migration inhibitory factor homologue J Infect Dis 195 2007 905 912 17299722 PMC2640454
  67. Kamir D Zierow S Leng L Cho Y Diaz Y Griffith J McDonald C Merk M Mitchell R A Trent J Chen Y Kwong Y K Xiong H Vermeire J Cappello M McMahon-Pratt D Walker J Bernhagen J Lolis E Bucala R A Leishmania ortholog of macrophage migration inhibitory factor modulates host macrophage responses J Immunol 180 2008 8250 8261 18523291 PMC2668862
  68. Tan T H Edgerton S A Kumari R McAlister M S Roe S M Nagl S Pearl L H Selkirk M E Bianco A E Totty N F Engwerda C Gray C A Meyer D J Rowe S M Macrophage migration inhibitory factor of the parasitic nematode Trichinella spiralis Biochem J 357 2001 373 383 11439086 PMC1221963
  69. Pearce E J M Kane C Sun J J Taylor J McKee A S Cervi L Th2 response polarization during infection with the helminth parasite Schistosoma mansoni Immunol Rev 201 2004 117 126 15361236
  70. Maizels R M Infections and allergy—helminths, hygiene and host immune regulation Curr Opin Immunol 17 2005 656 661 16202576
  71. Diaz A Allen J E Mapping immune response profiles: the emerging scenario from helminth immunology Eur J Immunol 37 2007 3319 3326 18000958

Cited by

Sorted by citations

Authors
Prieto-Lafuente, L., Gregory, W. F., Allen, J. E., & Maizels, R. M.
Affiliations
University of Edinburgh (GB)
Corresponding author
Maizels, Rick M
ORCID
Venue
Journal of Leukocyte Biology
Publisher
Oxford University Press (OUP)
Published
2009-01-29
Volume
85
Issue
5
Pages
844-854
ISSN
  • 0741-5400 (ISSN-L)
  • 1938-3673
DOI
10.1189/jlb.0808459
PMC
PMC2691607
OpenAlex
W2167285219
Cited by
79
References
1
Citations by year
2026: 1 · 2025: 3 · 2024: 1 · 2023: 5 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 4 · 2018: 3 · 2017: 5 · 2016: 2 · 2015: 4 · 2014: 3 · 2013: 8 · 2012: 5
FWCI
3.31
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • Journal of Leukocyte Biology (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
  • Research Explorer (The University of Manchester) (submittedVersion)
Funders
Wellcome Trust
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Macrophage Migration Inhibitory Factor
  • Health Sciences › Medicine › Infectious Diseases › Parasitic Diseases Research and Treatment
  • Life Sciences › Immunology and Microbiology › Parasitology › Parasites and Host Interactions
Keywords
macrophage migration inhibitory factor, Brugia malayi, filarial nematodes, alternative macrophage activation, IL-4, IL-4 receptor, Th2 immune response, chronic helminth infection, inflammatory cytokines, Ym1, arginase
MeSH terms
Animals, beta-N-Acetylhexosaminidases, Cells, Cultured, Macrophage Activation, Macrophage Migration-Inhibitory Factors, Macrophages, Mice, Inbred BALB C, Mice, Inbred C57BL, Interleukin-4, Up-Regulation, Brugia malayi, Mice, Knockout, Intramolecular Oxidoreductases, Receptors, Interleukin-4, Intercellular Signaling Peptides and Proteins, Lectins, 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