title: Elucidating the crosstalk mechanism between IFN-gamma and IL-6 via mathematical modelling.
abstract: BACKGROUND
  Interferon-gamma (IFN-gamma) and interleukin-6 (IL-6) are multifunctional cytokines that regulate immune responses, cell proliferation, and tumour development and progression, which frequently have functionally opposing roles. The cellular responses to both cytokines are activated via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. During the past 10 years, the crosstalk mechanism between the IFN-gamma and IL-6 pathways has been studied widely and several biological hypotheses have been proposed, but the kinetics and detailed crosstalk mechanism remain unclear.
  
  
  RESULTS
  Using established mathematical models and new experimental observations of the crosstalk between the IFN-gamma and IL-6 pathways, we constructed a new crosstalk model that considers three possible crosstalk levels: (1) the competition between STAT1 and STAT3 for common receptor docking sites; (2) the mutual negative regulation between SOCS1 and SOCS3; and (3) the negative regulatory effects of the formation of STAT1/3 heterodimers. A number of simulations were tested to explore the consequences of cross-regulation between the two pathways. The simulation results agreed well with the experimental data, thereby demonstrating the effectiveness and correctness of the model.
  
  
  CONCLUSIONS
  In this study, we developed a crosstalk model of the IFN-gamma and IL-6 pathways to theoretically investigate their cross-regulation mechanism. The simulation experiments showed the importance of the three crosstalk levels between the two pathways. In particular, the unbalanced competition between STAT1 and STAT3 for IFNR and gp130 led to preferential activation of IFN-gamma and IL-6, while at the same time the formation of STAT1/3 heterodimers enhanced preferential signal transduction by sequestering a fraction of the activated STATs. The model provided a good explanation of the experimental observations and provided insights that may inform further research to facilitate a better understanding of the cross-regulation mechanism between the two pathways.
authors: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors: Yun-feng
authors: YF
authors: Qi
authors: Yan-xin
authors: YX
authors: Huang
authors: Hong-yan
authors: HY
authors: Wang
authors: Yu
authors: Y
authors: Zhang
authors: Yong-li
authors: YL
authors: Bao
authors: Lu-guo
authors: LG
authors: Sun
authors: Yin
authors: Y
authors: Wu
authors: Chun-lei
authors: CL
authors: Yu
authors: Zhen-bo
authors: ZB
authors: Song
authors: Li-hua
authors: LH
authors: Zheng
authors: Ying
authors: Y
authors: Sun
authors: Guan-nan
authors: GN
authors: Wang
authors: Yu-xin
authors: YX
authors: Li
mesh_terms: D007371:Interferon-gamma / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D008954:Models, Biological; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma; D053612:Janus Kinases
references: EMBO J. 1995 Apr 3;14(7):1421-9
references: 7537214
references: Semin Cell Dev Biol. 2008 Aug;19(4):351-9
references: 18620071
references: J Biol Chem. 1996 May 31;271(22):12999-3007
references: 8662795
references: Cell. 1998 May 29;93(5):827-39
references: 9630226
references: Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10188-93
references: 10468584
references: Mol Cell Biol. 1999 Mar;19(3):2416-24
references: 10022928
references: ChemMedChem. 2011 Aug 1;6(8):1459-70
references: 21618433
references: Biochemistry. 2002 Jul 23;41(29):9229-36
references: 12119038
references: Oncogene. 2000 May 15;19(21):2638-44
references: 10851063
references: Biochem Biophys Res Commun. 2003 Feb 7;301(2):386-91
references: 12565872
references: Oncogene. 2005 Sep 22;24(42):6406-17
references: 16007195
references: J Biol Chem. 2004 Oct 1;279(40):41679-85
references: 15284232
references: Mol Cancer. 2012 Mar 16;11:12
references: 22423663
references: Cell. 2002 Apr;109 Suppl:S121-31
references: 11983158
references: Mol Cell Biol. 2002 Aug;22(16):5662-8
references: 12138178
references: Shock. 2002 Feb;17(2):83-90
references: 11837794
references: Essays Biochem. 2008;45:109-20
references: 18793127
references: IET Syst Biol. 2011 Jan;5(1):15
references: 21261398
references: Am J Physiol Cell Physiol. 2010 Aug;299(2):C354-62
references: 20484656
references: J Biol Chem. 2003 May 2;278(18):16117-28
references: 12591923
references: Biotechnol Bioeng. 2006 Dec 5;95(5):850-62
references: 16752369
references: Leukemia. 2009 Nov;23(11):2102-8
references: 19626047
references: Bioinformatics. 2006 Dec 15;22(24):3067-74
references: 17032683
references: Science. 1995 Mar 3;267(5202):1347-9
references: 7871432
references: Nature. 1998 Jul 9;394(6689):145-51
references: 9671298
references: Cell Signal. 2005 Dec;17(12):1542-50
references: 15935617
references: Eur J Cell Biol. 2012 Jun-Jul;91(6-7):486-95
references: 22138086
references: EMBO J. 2002 Feb 1;21(3):344-54
references: 11823427
references: Nat Immunol. 2003 Jun;4(6):540-5
references: 12754505
references: J Biol Chem. 1996 Mar 15;271(11):5961-4
references: 8626374
references: J Biol Chem. 2001 Jun 22;276(25):22086-9
references: 11306591
references: Cytokine Growth Factor Rev. 1997 Sep;8(3):189-206
references: 9462485
references: Immunity. 2000 Sep;13(3):287-90
references: 11021526
references: J Biol Chem. 2006 May 19;281(20):14111-8
references: 16571725
references: Genes Cells. 1999 Jun;4(6):339-51
references: 10421843
references: J Biol Chem. 2007 Jul 13;282(28):20059-63
references: 17502367
references: J Biol Chem. 2003 Jan 3;278(1):661-71
references: 12403768
references: J Leukoc Biol. 1999 Mar;65(3):391-6
references: 10080544
references: J Immunol. 2003 Nov 15;171(10):5034-41
references: 14607900
references: Nat Rev Mol Cell Biol. 2002 Sep;3(9):651-62
references: 12209125
references: In Silico Biol. 2007;7(2 Suppl):S81-90
references: 17822394
references: BMC Cancer. 2012 Jul 28;12:318
references: 22838736
references: Exp Cell Res. 2007 Nov 15;313(19):4015-24
references: 17880940
references: Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2003 Mar;19(2):106-8
references: 15151739
references: Nature. 1993 Dec 9;366(6455):580-3
references: 7504784
references: EMBO J. 2000 Nov 15;19(22):6196-206
references: 11080165
references: Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8043-7
references: 12060750
references: Cell. 1999 Sep 3;98(5):597-608
references: 10490099
references: J Neurochem. 2003 Oct;87(2):437-47
references: 14511121
references: J Leukoc Biol. 2004 Feb;75(2):163-89
references: 14525967
references: Nat Rev Immunol. 2003 Nov;3(11):900-11
references: 14668806
references: J Mol Cell Biol. 2012 Jun;4(3):125-6
references: 22652391
references: Biochem J. 2003 Aug 15;374(Pt 1):1-20
references: 12773095
references: Eur J Biochem. 1999 Feb;260(1):137-44
references: 10091593
references: Cytokine Growth Factor Rev. 2002 Apr;13(2):95-109
references: 11900986
references: EMBO J. 1994 Apr 1;13(7):1591-600
references: 8156998
references: Science. 1995 Mar 3;267(5202):1349-53
references: 7871433
references: Mol Cell Biol. 1999 Apr;19(4):2913-20
references: 10082558
references: FEBS Lett. 2005 Feb 14;579(5):1101-8
references: 15710397
references: Biochem J. 1998 Nov 1;335 ( Pt 3):557-65
references: 9794795
references: FEBS Lett. 2003 Jan 16;534(1-3):190-6
references: 12527385
references: Biochem J. 2004 Apr 1;379(Pt 1):199-208
references: 14690454