title: Low and moderate doses of ionizing radiation up to 2 Gy modulate transmigration and chemotaxis of activated macrophages, provoke an anti-inflammatory cytokine milieu, but do not impact upon viability and phagocytic function.
abstract: Benign painful and inflammatory diseases have been treated for decades with low/moderate doses of ionizing radiation (LD-X-irradiation). Tissue macrophages regulate initiation and resolution of inflammation by the secretion of cytokines and by acting as professional phagocytes. Having these pivotal functions, we were interested in how activated macrophages are modulated by LD-X-irradiation, also with regard to radiation protection issues and carcinogenesis. We set up an ex-vivo model in which lipopolysaccharide pre-activated peritoneal macrophages (pMΦ) of radiosensitive BALB/c mice, mimicking activated macrophages under inflammatory conditions, were exposed to X-irradiation from 0·01 Gy up to 2 Gy. Afterwards, the viability of the pMΦ, their transmigration and chemotaxis, the phagocytic behaviour, the secretion of inflammatory cytokines and underlying signalling pathways were determined. Exposure of pMΦ up to a single dose of 2 Gy did not influence their viability and phagocytic function, an important fact regarding radiation protection. However, significantly reduced migration, but increased chemotaxis of pMΦ after exposure to 0·1 or 0·5 Gy, was detected. Both might relate to the resolution of inflammation. Cytokine analyses revealed that, in particular, the moderate dose of 0·5 Gy applied in low-dose radiotherapy for inflammatory diseases results in an anti-inflammatory cytokine microenvironment of pMΦ, as the secretion of the proinflammatory cytokine interleukin (IL)-1β was reduced and that of the anti-inflammatory cytokine transforming growth factor (TGF)-β increased. Further, the reduced secretion of IL-1β correlated with reduced nuclear translocation of nuclear factor (NF)-κB p65, starting at exposure of pMΦ to 0·5 Gy of X-irradiation. We conclude that inflammation is modulated by LD-X-irradiation via changing the inflammatory phenotype of macrophages.
authors.affiliation: Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Wunderlich
authors.forename: A
authors.initials: A
authors.lastname: Ernst
authors.forename: F
authors.initials: F
authors.lastname: Rödel
authors.forename: R
authors.initials: R
authors.lastname: Fietkau
authors.forename: O
authors.initials: O
authors.lastname: Ott
authors.forename: K
authors.initials: K
authors.lastname: Lauber
authors.forename: B
authors.initials: B
authors.lastname: Frey
authors.forename: U S
authors.initials: US
authors.lastname: Gaipl
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000276:immunology / Q000528:radiation effects; D002633:Chemotaxis / Q000276:immunology* / Q000528:radiation effects*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology / Q000528:radiation effects; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D010587:Phagocytosis / Q000276:immunology* / Q000528:radiation effects*; D021381:Protein Transport; D011839:Radiation, Ionizing; D051996:Transcription Factor RelA / Q000378:metabolism; D014965:X-Rays
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D051996:Transcription Factor RelA
keywords: chemotaxis; cytokines; inflammation; macrophage; phagocytosis
references.citation: Cancer Lett. 2015 Jan 1;356(1):105-13
references.pmid: 24139966
references.citation: Methods Mol Biol. 2009;531:203-24
references.pmid: 19347320
references.citation: Am J Pathol. 1976 Nov;85(2):465-78
references.pmid: 136901
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21105-10
references.pmid: 22160723
references.citation: J Immunol. 2006 Apr 15;176(8):5023-32
references.pmid: 16585599
references.citation: Radiother Oncol. 2000 Mar;54(3):273-82
references.pmid: 10738086
references.citation: Am J Respir Cell Mol Biol. 1999 Apr;20(4):751-8
references.pmid: 10101008
references.citation: J Immunol. 2012 Jan 1;188(1):135-45
references.pmid: 22116825
references.citation: EMBO Mol Med. 2013 May;5(5):661-74
references.pmid: 23592557
references.citation: Int J Radiat Biol. 2002 Apr;78(4):315-25
references.pmid: 12020443
references.citation: Nat Immunol. 2013 Oct;14(10):986-95
references.pmid: 24048120
references.citation: Cell. 2010 Apr 2;141(1):39-51
references.pmid: 20371344
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Orthopade. 2004 Jan;33(1):56-62
references.pmid: 14747911
references.citation: J Exp Med. 1998 Jul 20;188(2):287-96
references.pmid: 9670041
references.citation: Int J Radiat Biol. 2003 Dec;79(12):993-1001
references.pmid: 14713577
references.citation: Immunity. 2013 Nov 14;39(5):874-84
references.pmid: 24184056
references.citation: Semin Immunopathol. 2007 Sep;29(3):213-29
references.pmid: 17703304
references.citation: Strahlenther Onkol. 2014 Mar;190(3):293-7
references.pmid: 24424629
references.citation: Nat Rev Immunol. 2008 Dec;8(12):958-69
references.pmid: 19029990
references.citation: Cancer Res. 2010 Jul 15;70(14):5728-39
references.pmid: 20570887
references.citation: Strahlenther Onkol. 2013 Feb;189(2):142-6
references.pmid: 23283585
references.citation: Radiat Res. 2009 Feb;171(2):219-24
references.pmid: 19267548
references.citation: Comp Med. 2007 Dec;57(6):574-80
references.pmid: 18246870
references.citation: Strahlenther Onkol. 1998 May;174(5):243-50
references.pmid: 9614952
references.citation: Strahlenther Onkol. 2012 Dec;188(12):1108-13
references.pmid: 23128898
references.citation: Nat Rev Mol Cell Biol. 2003 Feb;4(2):95-104
references.pmid: 12563287
references.citation: J Surg Res. 2011 May 15;167(2):e211-9
references.pmid: 19765725
references.citation: Mol Cell Biol. 1993 Oct;13(10):6231-40
references.pmid: 8413223
references.citation: Int J Radiat Biol. 2012 Oct;88(10):727-34
references.pmid: 22545750
references.citation: Strahlenther Onkol. 2003 Mar;179(3):158-66
references.pmid: 12627258
references.citation: Front Oncol. 2012 Sep 25;2:120
references.pmid: 23057008
references.citation: Curr Med Chem. 2012;19(12):1741-50
references.pmid: 22414082
references.citation: Cancer Cell. 2013 Nov 11;24(5):589-602
references.pmid: 24209604
references.citation: Semin Radiat Oncol. 2013 Oct;23(4):242-51
references.pmid: 24012338
references.citation: Nat Protoc. 2006;1(3):1458-61
references.pmid: 17406435
references.citation: Front Oncol. 2012 Sep 11;2:116
references.pmid: 22973558
references.citation: Mol Cell Biol. 1990 Apr;10(4):1498-506
references.pmid: 2181276
references.citation: Curr Top Microbiol Immunol. 2006;305:161-76
references.pmid: 16724805
references.citation: Nat Immunol. 2010 Oct;11(10):889-96
references.pmid: 20856220
references.citation: Int J Radiat Biol. 1999 Aug;75(8):995-1003
references.pmid: 10465365
references.citation: Cancer Metastasis Rev. 2010 Jun;29(2):309-16
references.pmid: 20405169
references.citation: Nat Rev Immunol. 2005 Dec;5(12):953-64
references.pmid: 16322748
references.citation: Nat Rev Cancer. 2008 Aug;8(8):618-31
references.pmid: 18633355
references.citation: Autoimmunity. 2013 Aug;46(5):323-8
references.pmid: 23215648
references.citation: Cell. 2010 Mar 19;140(6):883-99
references.pmid: 20303878
references.citation: J Radiat Res. 2009 May;50(3):223-31
references.pmid: 19398853
references.citation: J Immunol. 2010 Jul 1;185(1):642-52
references.pmid: 20530259
references.citation: N Engl J Med. 2010 Mar 11;362(10):875-85
references.pmid: 20220182
references.citation: Curr Opin Oncol. 2009 Jan;21(1):60-70
references.pmid: 19125020
references.citation: Strahlenther Onkol. 2013 Apr;189(4):329-34
references.pmid: 23443608
references.citation: Adv Immunol. 2013;120:69-103
references.pmid: 24070381
references.citation: Strahlenther Onkol. 2008 Jan;184(1):41-7
references.pmid: 18188522
references.citation: Autoimmunity. 2012 Dec;45(8):568-73
references.pmid: 22913458