The mechanism of action of interferon (IFN)-β therapy in multiple sclerosis (MS) is only partially known, and its efficacy changes with disease stage. In different forms of MS, we determined how IFN-β regulates mononuclear cell production of the important anti-inflammatory Th2 cytokine - IL-10, the Th1 cytokine - IFN-γ, and the brain-derived neurotrophic protein - BDNF. Activated T cells and monocytes from therapy-naïve patients secreted more IL-10 than healthy controls. During IFN-β therapy, however, T cells produced less IL-10. In vitro, IFN-β stimulated IL-10 production by activated T cells, but inhibited IL-10 secretion by activated monocytes, a richer source of IL-10 than T cells. The form of MS also affected cytokine production. IL-10 and BDNF levels in MNC were high during relapsing/remitting (RR) MS, but low in progressive MS. Surprisingly, IFN-β therapy increased BDNF levels in antidepressant-naïve patients, but BDNF was lower during concurrent antidepressant drug therapy, suggesting an interaction between MS, depression, and neurodegeneration. IFN-β in vitro strongly induced IL-10 and IFN-γ in activated T cells in RRMS, but not in progressive MS, suggesting IFN resistance. IFN-β effects are specific for disease state and immune subsets, possibly explaining why IFN-β therapy is most effective in early T cell-regulated RRMS, but less beneficial in progressive MS, where chronic plaques contain few T cells and high numbers of monocytes. Multiple Sclerosis 2007; 13: 459-470. http://msj.sagepub.com
Byskosh PV , Reder ATInterfleron-β eflflects on cytokine mRNA in peripheral mononuclear cells in multiple sclerosis . Mult Scler1996 ; 1: 262-69 .
2.
Rieckmann P.The eflflects ofl IFN-β on cytokines and immune responses. In Reder AT ed. Interferon therapy of multiple sclerosis. Marcel Dekker, Inc. , 1997 : 161-91.
3.
Noseworthy JH , Lucchinetti C. , Rodriguez M. , Weinshenker BGMultiple sclerosis . N Engl J Med2000; 343: 938-52 .
4.
Reder ATMultiple sclerosis. In Gilman S ed. Neurobase, Medlink neurology. Medlink Corporation , www.medlink.com, 2004.
5.
Boutros T. , Croze E. , Yong VWInterfleron-β is a potent promoter ofl nerve growth flactor production by astrocytes . J Neurochem1997; 69: 939-46 .
6.
Sarchielli P. , Greco L. , Stipa A. et al. Brain-derived neurotrophic flactor in patients with multiple sclerosis . J Neuroimmunol2002; 132: 180-88 .
7.
Schori H. , Kipnis J. , Yoles E. et al. Vaccination flor protection ofl retinal ganglion cells against death flrom glutamate cytotoxicity and ocular hypertension: implications flor glaucoma . Proc Natl Acad Sci USA2001; 98: 3398-403 .
8.
Howard M. , O'Garra A. , Ishida H. et al. Biological properties ofl interleukin 10 . J Clin Immunol1992; 12: 239-47 .
9.
Feng X. , Yau D. , Holbrook C. , Reder ATType I interflerons inhibit interleukin-10 production in activated human monocytes and stimulate IL-10 in T cells: implications flor Th1-mediated diseases . J Interferon Cytokine Res2002; 22: 311-19 .
10.
de Jong BA , Schrijver HM , Huizinga Twj et al. Innate production ofl interleukin-10 and tumor necrosis flactor aflflects the risk ofl multiple sclerosis . Ann Neurol2000; 48: 641-46 .
11.
Rieckmann P. , Albrecht M. , Kitze B. et al. Cytokine mRNA levels in mononuclear blood cells flrom patients with multiple sclerosis . Neurology1994; 44: 1523-26 .
12.
Salmaggi A. , Dufour A. , Eoli M. et al. Low serum interleukin-10 levels in multiple sclerosis: flurther evidence flor decreased systemic immunosuppression?J Neurol1996; 243: 13-17 .
13.
van Boxel-Dezaire Ahh , Hoff Scj , van Oosten BW et al. Decreased interleukin-10 and increased interleukin-12p40 mRNA are associated with disease activity and characterize diflflerent disease stages in multiple sclerosis . Ann Neurol1999; 45: 695-703 .
14.
Waubant E. , Gee L. , Bacchetti P. et al. Relationship between serum levels ofl IL-10, MRI activity and interfleron beta-1a therapy in patients with relapsing remitting MS . J Neuroimmunol2001; 112: 139-45 .
15.
Panitch HS , Hirsch RL , Schindler J. , Johnson KPTreatment ofl multiple sclerosis with gamma interfleron: exacerbations associated with activation ofl the immune system . Neurology1987; 37: 1097-102 .
16.
Dettke M. , Scheidt P. , Prange H. , Kirchner H.Correlation between interfleron production and clinical disease activity in patients with multiple sclerosis . J Clin Immunol1997; 17: 293-99 .
17.
Laudiero LB , Aloe L. , Levi-Montalcini R. et al. Multiple sclerosis patients express increased levels ofl β-nerve growth flactor in cerebrospinal fluid . Neurosci Lett1992; 147: 9-12 .
18.
Kerschensteiner M. , Gallmeier E. , Behrens L. et al. Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic flactor in vitro and in inflammatory brain lesions: a neuroprotective role ofl inflammation . J Exp Med1999; 189: 865-70 .
19.
Schulte-Herbruggen O. , Nassenstein C. , Lommatzsch M. et al. Tumor necrosis flactor-α and interleukin-6 regulate secretion ofl brain-derived neurotrophic flactor in human monocytes . J Neuroimmunol2005; 160: 204-209 .
20.
Kreitman RR , Blanchette F.On the horizon: possible neuroprotective role flor glatiramer acetate . Mult Scler2004 ; 10: S81-S89 .
Noronha A. , Toscas A. , Jensen MAInterfleron beta augments suppressor cell flunction in multiple sclerosis . Ann Neurol1990; 27: 207-10 .
23.
Rieckmann P. , Günther A. , Bitsch A. , Weber F.Pentoxiflylline synergizes with interfleron-β and reduces its side eflflects in patients with multiple sclerosis . Neurology1996; 46: A135-36 .
24.
Rudick RA , Ransohoff RM , Peppler R. et al. Interfleron beta induces interleukin-10 expression: relevance to multiple sclerosis . Ann Neurol1996; 40: 618-27 .
25.
Rudick RA , Ransohoff RM , Lee J-C. et al. In vivo eflflects ofl interfleron beta-1a on immunosuppressive cytokines in multiple sclerosis . Neurology1998; 50: 1294-300 .
26.
Porrini AM , Gambi D. , Reder ATInterfleron eflflects on interleukin-10 secretion. Mononuclear cell response to interleukin-10 is normal in multiple sclerosis patients . J Neuroimmunol1995; 61: 27-34 .
27.
Huang Y-M. , Hussien Y. , Jin Y-P. et al. Multiple sclerosis: deficient in vitro responses ofl blood mononuclear cells to IFN-β . Acta Neurol Scand2001 ; 104: 249-56 .
28.
Curreli S. , Romerio F. , Secchiero P. , Zella D.IFN-α2b increases interleukin-10 expression in primary activated human CD8+ T cells . J Interferon Cytokine Res2002 ; 22: 1167-73 .
29.
Caggiula M. , Batocchi AP , Frisullo G. et al. Neurotrophic flactors in relapsing remitting and secondary progressive multiple sclerosis patients during interfleron beta therapy . Clin Immunol2006; 118: 77-82 .
30.
Poser CM , Paty DW , Scheinberg L.New diagnostic criteria flor multiple sclerosis: guidelines flor research protocols . Ann Neurol1983; 13: 227-31 .
31.
Feng X. , Petraglia AL , Chen M. et al. Low expression ofl interfleron-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation ofl STAT1 . J Neuroimmunol2002; 129: 105-15 .
32.
Byrnes AA , McArthur JC , Karp CLInterfleron-β therapy flor multiple sclerosis induces reciprocal changes in interleukin-12 and interleukin-10 production . Ann Neurol2002; 51: 165-74 .
33.
Fillatreau S. , Sweenie CH , McGeachy MJ et al. B cells regulate autoimmunity by provision ofl IL-10 . Nat Immunol2002; 3: 944-50 .
34.
Ahn J. , Feng X. , Patel N. et al. Abnormal levels ofl interfleron-gamma receptors in active multiple sclerosis are normalized by IFN-β therapy: implications flor control ofl apoptosis . Front Biosci2004; 9: 1547-55 .
35.
Witt PLPharmacokinetics ofl interfleron-β and the biological markers it induces . In Reder AT ed. Interferon therapy of multiple sclerosis. Marcel Dekker, Inc. , 1997: 77-93.
36.
Noronha A. , Toscas A. , Jensen MAInterfleron β decreases T cell activation and interfleron γ production in multiple sclerosis . J Neuroimmunol1993 ; 46: 145-54 .
37.
Reder AT , Antel JP , Oger JJ et al. Low T8 antigen density on lymphocytes in active multiple sclerosis . Ann Neurol1984; 16: 242-49 .
38.
Beck J. , Rondot P. , Catinot L. et al. Increased production ofl interfleron gamma and tumor necrosis flactor precedes clinical maniflestation in multiple sclerosis: do cytokines trigger oflfl exacerbations?Acta Neurol Scand1988; 78: 318-23 .
39.
Nibuya M. , Morinobu S. , Duman RSRegulation ofl BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments . J Neurosci1995; 15: 7539-47 .
40.
Arnason Bgw.Depression in MS - neuroimmunological perspective . Neuroimmune Biol2005; 9: (in press).
41.
Rep Mhg , Schrijver HM , van Lopik T. et al. Interfleron (IFN)-β treatment enhances CD95 and interleukin 10 expression but reduces interfleron-γ producing T cells in MS patients . J Neuroimmunol1999; 96: 92-100 .
42.
Nicoletti F. , Di Marco R. , Patti F. et al. Short-term treatment ofl relapsing remitting multiple sclerosis patients with interfleron (IFN)-β1B transiently increases the blood levels ofl interleukin (IL)-6, IL-10 and IFN-γ without significantly modiflying those ofl IL-1β, IL-2, IL-4 and tumour necrosis flactor-α . Cytokine2000; 12: 682-87 .
Gayo A. , Mozo L. , Suarez A. et al. Long-term eflflect ofl IFNβ1b treatment on the spontaneous and induced expression ofl IL-10 and TGFβ1 in MS patients . J Neurol Sci2000; 179: 43-49 .
45.
Filion LG , Granziani-Bowering G. , Matusevicius D. , Freedman MSMonocyte-derived cytokines in multiple sclerosis . Clin Exp Immunol2003; 131: 324-34 .
46.
Finkelman FD , Svetic A. , Gresser I. et al. Regulation by interfleron α ofl immunoglobulin isotype selection and lymphokine production in mice . J Exp Med1991; 174: 1179-88 .
47.
Brinkmann V. , Geiger T. , Alkan S. , Heusser CHInterfleron α increases the flrequency ofl interfleron γ-producing human CD4+ T cells . J Exp Med1993; 178: 1655-63 .
48.
Dayal AS , Jensen MA , Lledo A. , Arnason Bgw.Interfleron-gamma-secreting cells in multiple sclerosis patients treated with interfleron beta-1b . Neurology1995; 45: 2173-77 .
49.
Revel M. , Chebath J. , Mangelus M. et al. Antagonism ofl interfleron beta on interfleron gamma: inhibition ofl signal transduction in vitro and reduction ofl serum levels in multiple sclerosis patients . Mult Scler1995; 1: S5-11 .
50.
Perini P. , Wadhwa M. , Buttarello M. et al. Eflflect ofl IFNβ and anti-IFNβ antibodies on NK cells in multiple sclerosis patients . J Neuroimmunol2000; 105: 91-95 .
51.
Lassmann H. , Suchanek G. , Ozawa K.Histopathology and the blood-cerebrospinal fluid barrier in multiple sclerosis . Ann Neurol1994; 36: S42-46 .
52.
Kuhlmann T. , Lingfeld G. , Bitsch A. et al. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time . Brain2002; 125: 2202-12 .
53.
Boven LA , Van Meurs M. , Van Zwam M. et al. Myelin-laden macrophages are anti-inflammatory, consistent with floam cells in multiple sclerosis . Brain2006 ; 129: 517-26 .
54.
Panitch HS , MS NASGoIB-biSP. Interfleron beta-1b in secondary progressive MS: results flrom a 3-year controlled study . Neurology2004; 63: 1788-95 .
55.
Hulshof S. , Montagne L. , De Groot Cja , Van Der Valk P.Cellular localization and expression patterns ofl interleukin-10, interleukin-4, and their receptors in multiple sclerosis lesions . Glia2002; 38: 24-35 .
56.
Gielen A. , Khademi M. , Muhallab S. et al. Increased brain-derived neurotrophic flactor expression in white blood cells ofl relapsing-remitting multiple sclerosis patients . Scand J Immunol2003; 57: 493-97 .
57.
Petereit HF , Lindemann H. , Schoppe S.Eflflect ofl immunomodulatory drugs on in vitro production ofl brain-derived neurotrophic flactor . Mult Scler2003; 9: 16-20 .
58.
Batchelor PE , Porritt MJ , Martinello P. et al. Macrophages and microglia produce local trophic gradients that stimulate axonal sprouting toward but not beyond the wound edge . Mol Cell Neurosci2002; 21: 436-53 .
59.
Correale J. , Gilmore W. , Lopez J. et al. Deflective postthymic tolerance mechanisms during the chronic progressive stage ofl multiple sclerosis . Nat Med1996; 2: 1354-60 .
60.
Kracke A. , von Wussow P. , Al Masri AN et al. Mx proteins in blood leukocytes flor monitoring interfleron beta-1b therapy in patients with MS . Neurology2000; 54: 193-99 .
61.
Porrini AmReder ATIFN-γ, IFN-β and PGE1 aflflect monokine secretion: relevance to monocyte activation in multiple sclerosis . Cell Immunol1994; 157: 428-38 .
62.
Toyomoto M. , Ohta M. , Okumura K. et al. Prostaglandins are powerflul inducers ofl NGF and BDNF production in mouse astrocyte cultures . FEBS Lett2004 ; 562: 211-15 .
63.
Weber F. , Polak T. , Günther A. et al. Synergistic immunomodulatory eflflects ofl interfleron-β1b and the phosphodiesterase inhibitor pentoxiflylline in patients with relapsing-remitting multiple sclerosis . Ann Neurol1998; 44: 27-34 .
64.
Reder AT , Thapar M. , Sapugay AM , Jensen MAProstaglandins and inhibitors ofl arachidonate metabolism suppress experimental allergic encephalomyelitis . J Neuroimmunol1994; 54: 117-27 .
65.
Chelmicka-Schorr E. , Arnason Bgw.Interactions between the sympathetic nervous system and the immune system . Brain Behav Immunol1999; 13: 271-78 .
