Recombinant IL-6 treatment protects mice from organ specific autoimmune disease by IL-6 classical signalling-dependent IL-1ra induction

Unni Krishna S.R.L. Samavedam; Kathrin Kalies; Jürgen Scheller; Hengameh Sadeghi; Yask Gupta; Marcel F. Jonkman; Enno Schmidt; Jürgen Westermann; Detlef Zillikens; Stefan Rose-John; Ralf J. Ludwig

doi:10.1016/j.jaut.2012.08.002

Recombinant IL-6 treatment protects mice from organ specific autoimmune disease by IL-6 classical signalling-dependent IL-1ra induction

Unni Krishna S.R.L. Samavedam^*, Kathrin Kalies, Jürgen Scheller, Hengameh Sadeghi, Yask Gupta, Marcel F. Jonkman, Enno Schmidt, Jürgen Westermann, Detlef Zillikens, Stefan Rose-John, Ralf J. Ludwig

^*Corresponding author for this work

47 Citations (Scopus)

Abstract

Cytokines are key regulators of physiological inflammatory responses, while aberrant cytokine expression contributes to pathogenesis of autoimmune diseases. We noted increased IL-6 levels in human and murine epidermolysis bullosa acquisita (EBA), a prototypic organ-specific autoimmune bullous dermatoses (AIBD) induced by autoantibodies to type VII collagen (COL7). In contrast to rheumatoid arthritis, blockade of IL-6 led to strikingly enhanced experimental EBA, while treatment with recombinant IL-6 was protective. This was due to classical IL-6 signalling and independent of IL-6 trans-signalling, as treatment of mice with sgp130Fc had no impact on EBA manifestation. Induction of EBA in mice led to increased IL-1ra levels in skin and serum, while blockade of IL-6 completely inhibited IL-1ra expression induced by autoantibodies to COL7. In line, treatment of mice with EBA with recombinant IL-6 induced IL-1ra concentrations exceeding those of untreated animals with EBA, and IL-1ra (anakinra) administration significantly impaired experimental EBA induction. We here identified a novel anti-inflammatory pathway in an organ-specific autoimmune disease. Modulation of this IL-1ra pathway by classical IL-6 signalling demonstrates anti-inflammatory and protective activities of IL-6 in vivo.

Original language	English
Journal	Journal of Autoimmunity
Volume	40
Issue number	1
Pages (from-to)	74-85
Number of pages	12
ISSN	0896-8411
DOIs	https://doi.org/10.1016/j.jaut.2012.08.002
Publication status	Published - 01.02.2013

Funding

We thank Prof. Cem Gabay and Dr. Celine Lamacchia (Division of Rheumatology, University Hospitals of Geneva, Geneva, Switzerland) for critical discussion and providing primer sequences for IL-1ra. This study was supported by the following grants: Excellence Cluster “Inflammation at Interfaces” ( EXC306/1 ), Graduiertenkolleg “Modulation of Autoimmunity” ( GRK1727/1 ) and LU877/5-1 , all provided by the Deutsche Forschungsgemeinschaft , as well as Focus Program “Autoimmunity” at the University of Lübeck and the Doktor Robert-Pfleger Foundation . The contribution of JS and SRJ was supported by the Deutsche Forschungsgemeinschaft (SFB877, projects A1, A2). Appendix A

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Samavedam, U. K. S. R. L., Kalies, K., Scheller, J., Sadeghi, H., Gupta, Y., Jonkman, M. F., Schmidt, E., Westermann, J., Zillikens, D., Rose-John, S., & Ludwig, R. J. (2013). Recombinant IL-6 treatment protects mice from organ specific autoimmune disease by IL-6 classical signalling-dependent IL-1ra induction. Journal of Autoimmunity, 40(1), 74-85. https://doi.org/10.1016/j.jaut.2012.08.002

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title = "Recombinant IL-6 treatment protects mice from organ specific autoimmune disease by IL-6 classical signalling-dependent IL-1ra induction",

abstract = "Cytokines are key regulators of physiological inflammatory responses, while aberrant cytokine expression contributes to pathogenesis of autoimmune diseases. We noted increased IL-6 levels in human and murine epidermolysis bullosa acquisita (EBA), a prototypic organ-specific autoimmune bullous dermatoses (AIBD) induced by autoantibodies to type VII collagen (COL7). In contrast to rheumatoid arthritis, blockade of IL-6 led to strikingly enhanced experimental EBA, while treatment with recombinant IL-6 was protective. This was due to classical IL-6 signalling and independent of IL-6 trans-signalling, as treatment of mice with sgp130Fc had no impact on EBA manifestation. Induction of EBA in mice led to increased IL-1ra levels in skin and serum, while blockade of IL-6 completely inhibited IL-1ra expression induced by autoantibodies to COL7. In line, treatment of mice with EBA with recombinant IL-6 induced IL-1ra concentrations exceeding those of untreated animals with EBA, and IL-1ra (anakinra) administration significantly impaired experimental EBA induction. We here identified a novel anti-inflammatory pathway in an organ-specific autoimmune disease. Modulation of this IL-1ra pathway by classical IL-6 signalling demonstrates anti-inflammatory and protective activities of IL-6 in vivo.",

author = "Samavedam, \{Unni Krishna S.R.L.\} and Kathrin Kalies and J{\"u}rgen Scheller and Hengameh Sadeghi and Yask Gupta and Jonkman, \{Marcel F.\} and Enno Schmidt and J{\"u}rgen Westermann and Detlef Zillikens and Stefan Rose-John and Ludwig, \{Ralf J.\}",

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Samavedam, UKSRL, Kalies, K, Scheller, J, Sadeghi, H, Gupta, Y, Jonkman, MF, Schmidt, E , Westermann, J, Zillikens, D, Rose-John, S & Ludwig, RJ 2013, 'Recombinant IL-6 treatment protects mice from organ specific autoimmune disease by IL-6 classical signalling-dependent IL-1ra induction', Journal of Autoimmunity, vol. 40, no. 1, pp. 74-85. https://doi.org/10.1016/j.jaut.2012.08.002

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T1 - Recombinant IL-6 treatment protects mice from organ specific autoimmune disease by IL-6 classical signalling-dependent IL-1ra induction

AU - Samavedam, Unni Krishna S.R.L.

AU - Kalies, Kathrin

AU - Scheller, Jürgen

AU - Sadeghi, Hengameh

AU - Gupta, Yask

AU - Jonkman, Marcel F.

AU - Schmidt, Enno

AU - Westermann, Jürgen

AU - Zillikens, Detlef

AU - Rose-John, Stefan

AU - Ludwig, Ralf J.

PY - 2013/2/1

Y1 - 2013/2/1

N2 - Cytokines are key regulators of physiological inflammatory responses, while aberrant cytokine expression contributes to pathogenesis of autoimmune diseases. We noted increased IL-6 levels in human and murine epidermolysis bullosa acquisita (EBA), a prototypic organ-specific autoimmune bullous dermatoses (AIBD) induced by autoantibodies to type VII collagen (COL7). In contrast to rheumatoid arthritis, blockade of IL-6 led to strikingly enhanced experimental EBA, while treatment with recombinant IL-6 was protective. This was due to classical IL-6 signalling and independent of IL-6 trans-signalling, as treatment of mice with sgp130Fc had no impact on EBA manifestation. Induction of EBA in mice led to increased IL-1ra levels in skin and serum, while blockade of IL-6 completely inhibited IL-1ra expression induced by autoantibodies to COL7. In line, treatment of mice with EBA with recombinant IL-6 induced IL-1ra concentrations exceeding those of untreated animals with EBA, and IL-1ra (anakinra) administration significantly impaired experimental EBA induction. We here identified a novel anti-inflammatory pathway in an organ-specific autoimmune disease. Modulation of this IL-1ra pathway by classical IL-6 signalling demonstrates anti-inflammatory and protective activities of IL-6 in vivo.

AB - Cytokines are key regulators of physiological inflammatory responses, while aberrant cytokine expression contributes to pathogenesis of autoimmune diseases. We noted increased IL-6 levels in human and murine epidermolysis bullosa acquisita (EBA), a prototypic organ-specific autoimmune bullous dermatoses (AIBD) induced by autoantibodies to type VII collagen (COL7). In contrast to rheumatoid arthritis, blockade of IL-6 led to strikingly enhanced experimental EBA, while treatment with recombinant IL-6 was protective. This was due to classical IL-6 signalling and independent of IL-6 trans-signalling, as treatment of mice with sgp130Fc had no impact on EBA manifestation. Induction of EBA in mice led to increased IL-1ra levels in skin and serum, while blockade of IL-6 completely inhibited IL-1ra expression induced by autoantibodies to COL7. In line, treatment of mice with EBA with recombinant IL-6 induced IL-1ra concentrations exceeding those of untreated animals with EBA, and IL-1ra (anakinra) administration significantly impaired experimental EBA induction. We here identified a novel anti-inflammatory pathway in an organ-specific autoimmune disease. Modulation of this IL-1ra pathway by classical IL-6 signalling demonstrates anti-inflammatory and protective activities of IL-6 in vivo.

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SN - 0896-8411

VL - 40

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JO - Journal of Autoimmunity

JF - Journal of Autoimmunity

IS - 1

ER -

Recombinant IL-6 treatment protects mice from organ specific autoimmune disease by IL-6 classical signalling-dependent IL-1ra induction

Abstract

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