Universität zu Köln

Shimabukuro-Vornhagen, Alexander ORCID: 0000-0002-2351-7294, Zoghi, Shahram, Liebig, Tanja M., Wennhold, Kerstin ORCID: 0000-0001-5539-7226, Chemitz, Jens, Draube, Andreas, Kochanek, Matthias, Blaschke, Florian, Pallasch, Christian, Holtick, Udo, Scheid, Christof, Theurich, Sebastian ORCID: 0000-0001-5706-8258, Hallek, Michael and von Bergwelt-Baildon, Michael S. (2014). Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity. J. Immunol., 193 (10). S. 5294 - 5306. BETHESDA: AMER ASSOC IMMUNOLOGISTS. ISSN 1550-6606

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Abstract

Ab-independent effector functions of B cells, such as Ag presentation and cytokine production, have been shown to play an important role in a variety of immune-mediated conditions such as autoimmune diseases, transplant rejection, and graft-versus-host disease. Most current immunosuppressive treatments target T cells, are relatively unspecific, and result in profound immunosuppression that places patients at an increased risk of developing severe infections and cancer. Therapeutic strategies, which interfere with B cell activation, could therefore be a useful addition to the current immunosuppressive armamentarium. Using a transcriptomic approach, we identified upregulation of genes that belong to the mevalonate pathway as a key molecular event following CD40-mediated activation of B cells. Inhibition of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway, by lipophilic statins such as simvastatin and atorvastatin resulted in a specific inhibition of B cell activation via CD40 and impaired their ability to act as stimulatory APCs for allospecific T cells. Mechanistically, the inhibitory effect resulted from the inhibition of protein geranylgeranylation subsequent to the depletion of mevalonate, the metabolic precursor for geranylgeranyl. Thus, inhibition of geranylgeranylation either directly through geranylgeranyl transferase inhibitors or indirectly through statins represents a promising therapeutic approach for the treatment of diseases in which Ag presentation by B cells plays a role.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Shimabukuro-Vornhagen, Alexander UNSPECIFIED orcid.org/0000-0002-2351-7294 UNSPECIFIED Zoghi, Shahram UNSPECIFIED UNSPECIFIED UNSPECIFIED Liebig, Tanja M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wennhold, Kerstin UNSPECIFIED orcid.org/0000-0001-5539-7226 UNSPECIFIED Chemitz, Jens UNSPECIFIED UNSPECIFIED UNSPECIFIED Draube, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Kochanek, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Blaschke, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Pallasch, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Holtick, Udo UNSPECIFIED UNSPECIFIED UNSPECIFIED Scheid, Christof UNSPECIFIED UNSPECIFIED UNSPECIFIED Theurich, Sebastian UNSPECIFIED orcid.org/0000-0001-5706-8258 UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED von Bergwelt-Baildon, Michael S. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-423278
DOI:	10.4049/jimmunol.1203436
Journal or Publication Title:	J. Immunol.
Volume:	193
Number:	10
Page Range:	S. 5294 - 5306
Date:	2014
Publisher:	AMER ASSOC IMMUNOLOGISTS
Place of Publication:	BETHESDA
ISSN:	1550-6606
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language VERSUS-HOST-DISEASE; HMG-COA REDUCTASE; ANTIGEN-PRESENTING CELLS; TRANSPLANT RECIPIENTS; DENDRITIC CELLS; IN-VIVO; CHRONIC GVHD; TGF-BETA; STATINS; EXPRESSION Multiple languages Immunology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42327