Interferon-gamma regulates cathepsin G activity in microglia-derived lysosomes and controls the proteolytic processing of myelin basic protein in vitro

Timo Burster, Alexander Beck, Simone Poeschel, Anita Øren, Daniel Baechle, Michael Reich, Olaf Roetzschke, Kirsten Falk, Bernhard O Boehm, Sawsan Youssef, Hubert Kalbacher, Herman Overkleeft, Eva Tolosa, Christoph Driessen

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The serine protease cathepsin (Cat) G dominates the proteolytic processing of the multiple sclerosis (MS)-associated autoantigen myelin basic protein (MBP) in lysosomes from primary human B cells and dendritic cells. This is in contrast to B-lymphoblastoid cell lines, where the asparagine endopeptidase (AEP) is responsible for this task. We have analysed microglia-derived lysosomal proteases for their ability to process MBP in vitro. In lysosomes derived from primary murine microglia, CatD, CatS, AEP and CatG were involved in the processing of MBP. Interestingly, when microglia were treated with interferon-gamma to mimic a T helper type 1-biased cytokine milieu in MS, CatG was drastically down-regulated, in contrast to CatS, CatB, CatL, CatD or AEP. This resulted in significantly increased stability of MBP and a selective lack of CatG-derived proteolytic fragments; however, it did not affect the gross pattern of MBP processing. Inhibition of serine proteases eliminated the processing differences between lysosomal extracts from resting microglia compared to interferon-stimulated microglia. Thus, the cytokine environment modulates lysosomal proteases in microglia by a selective down-regulation of CatG, leading to decreased MBP-processing by microglia-derived lysosomal proteases in vitro.

Original languageEnglish
Pages (from-to)82-93
Number of pages12
JournalImmunology
Volume121
Issue number1
DOIs
Publication statusPublished - May 2007
Externally publishedYes

Fingerprint

Cathepsin G
Myelin Basic Protein
Microglia
Lysosomes
Interferon-gamma
Endopeptidases
Asparagine
Peptide Hydrolases
Serine Proteases
Multiple Sclerosis
Cats
Cytokines
Autoantigens
In Vitro Techniques
Dendritic Cells
Interferons
B-Lymphocytes
Down-Regulation
Cell Line

Keywords

  • Animals
  • Antigen Presentation
  • Autoantigens
  • Cathepsin G
  • Cathepsins
  • Down-Regulation
  • Interferon-gamma
  • Lysosomes
  • Mice
  • Mice, Inbred Strains
  • Microglia
  • Myelin Basic Protein
  • Phenylmethylsulfonyl Fluoride
  • Protease Inhibitors
  • Serine Endopeptidases
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Interferon-gamma regulates cathepsin G activity in microglia-derived lysosomes and controls the proteolytic processing of myelin basic protein in vitro. / Burster, Timo; Beck, Alexander; Poeschel, Simone; Øren, Anita; Baechle, Daniel; Reich, Michael; Roetzschke, Olaf; Falk, Kirsten; Boehm, Bernhard O; Youssef, Sawsan; Kalbacher, Hubert; Overkleeft, Herman; Tolosa, Eva; Driessen, Christoph.

In: Immunology, Vol. 121, No. 1, 05.2007, p. 82-93.

Research output: Contribution to journalArticle

Burster, T, Beck, A, Poeschel, S, Øren, A, Baechle, D, Reich, M, Roetzschke, O, Falk, K, Boehm, BO, Youssef, S, Kalbacher, H, Overkleeft, H, Tolosa, E & Driessen, C 2007, 'Interferon-gamma regulates cathepsin G activity in microglia-derived lysosomes and controls the proteolytic processing of myelin basic protein in vitro', Immunology, vol. 121, no. 1, pp. 82-93. https://doi.org/10.1111/j.1365-2567.2007.02540.x
Burster, Timo ; Beck, Alexander ; Poeschel, Simone ; Øren, Anita ; Baechle, Daniel ; Reich, Michael ; Roetzschke, Olaf ; Falk, Kirsten ; Boehm, Bernhard O ; Youssef, Sawsan ; Kalbacher, Hubert ; Overkleeft, Herman ; Tolosa, Eva ; Driessen, Christoph. / Interferon-gamma regulates cathepsin G activity in microglia-derived lysosomes and controls the proteolytic processing of myelin basic protein in vitro. In: Immunology. 2007 ; Vol. 121, No. 1. pp. 82-93.
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AU - Beck, Alexander

AU - Poeschel, Simone

AU - Øren, Anita

AU - Baechle, Daniel

AU - Reich, Michael

AU - Roetzschke, Olaf

AU - Falk, Kirsten

AU - Boehm, Bernhard O

AU - Youssef, Sawsan

AU - Kalbacher, Hubert

AU - Overkleeft, Herman

AU - Tolosa, Eva

AU - Driessen, Christoph

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N2 - The serine protease cathepsin (Cat) G dominates the proteolytic processing of the multiple sclerosis (MS)-associated autoantigen myelin basic protein (MBP) in lysosomes from primary human B cells and dendritic cells. This is in contrast to B-lymphoblastoid cell lines, where the asparagine endopeptidase (AEP) is responsible for this task. We have analysed microglia-derived lysosomal proteases for their ability to process MBP in vitro. In lysosomes derived from primary murine microglia, CatD, CatS, AEP and CatG were involved in the processing of MBP. Interestingly, when microglia were treated with interferon-gamma to mimic a T helper type 1-biased cytokine milieu in MS, CatG was drastically down-regulated, in contrast to CatS, CatB, CatL, CatD or AEP. This resulted in significantly increased stability of MBP and a selective lack of CatG-derived proteolytic fragments; however, it did not affect the gross pattern of MBP processing. Inhibition of serine proteases eliminated the processing differences between lysosomal extracts from resting microglia compared to interferon-stimulated microglia. Thus, the cytokine environment modulates lysosomal proteases in microglia by a selective down-regulation of CatG, leading to decreased MBP-processing by microglia-derived lysosomal proteases in vitro.

AB - The serine protease cathepsin (Cat) G dominates the proteolytic processing of the multiple sclerosis (MS)-associated autoantigen myelin basic protein (MBP) in lysosomes from primary human B cells and dendritic cells. This is in contrast to B-lymphoblastoid cell lines, where the asparagine endopeptidase (AEP) is responsible for this task. We have analysed microglia-derived lysosomal proteases for their ability to process MBP in vitro. In lysosomes derived from primary murine microglia, CatD, CatS, AEP and CatG were involved in the processing of MBP. Interestingly, when microglia were treated with interferon-gamma to mimic a T helper type 1-biased cytokine milieu in MS, CatG was drastically down-regulated, in contrast to CatS, CatB, CatL, CatD or AEP. This resulted in significantly increased stability of MBP and a selective lack of CatG-derived proteolytic fragments; however, it did not affect the gross pattern of MBP processing. Inhibition of serine proteases eliminated the processing differences between lysosomal extracts from resting microglia compared to interferon-stimulated microglia. Thus, the cytokine environment modulates lysosomal proteases in microglia by a selective down-regulation of CatG, leading to decreased MBP-processing by microglia-derived lysosomal proteases in vitro.

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KW - Autoantigens

KW - Cathepsin G

KW - Cathepsins

KW - Down-Regulation

KW - Interferon-gamma

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KW - Mice

KW - Mice, Inbred Strains

KW - Microglia

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KW - Phenylmethylsulfonyl Fluoride

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KW - Serine Endopeptidases

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

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