Universität zu Köln

Knoke, Kristin, Rongisch, Robert R., Grzes, Katarzyna M., Schwarz, Roman, Lorenz, Beate ORCID: 0000-0001-7880-6272, Yogev, Nir, Pearce, Erika L., Pearce, Edward J., Kofler, David M. and Fabri, Mario (2022). Tofacitinib Suppresses IL-10/IL-10R Signaling and Modulates Host Defense Responses in Human Macrophages. J. Invest. Dermatol., 142 (3 PT A). S. 559 - 577. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1523-1747

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Abstract

Jak inhibitors are increasingly used in dermatology. Despite broad inhibitory effects on cytokine signaling cascades, they only modestly increase the risk for infectious diseases. To address the molecular mechanisms underlying this unexpected clinical observation, we investigated how tofacintib (tofa), a first-in-class Jak inhibitor, regulates host defense responses in toll-like receptor 4-activated human macrophages. Specifically, we asked whether tofa inhibits anti-inflammatory IL-10 signaling, thereby counteracting the downregulation of inflammatory, host-protective pathways. We found that tofa blocked macrophage responses to IL-10 at the level of signal transducer and activator of transcription 3 phosphorylation. Furthermore, toll-like receptor 4-induced, autocrine/paracrine IL-10/IL-10R activation promoted the expression of hepcidin, the master regulator of iron metabolism, resulting in intracellular iron sequestration. In contrast, autocrine/paracrine IL-10/IL-10R activation repressed the expression of cathelicidin antimicrobial peptide as well as antigen-presenting molecules, thus together, inducing a pathogen-favoring environment. Although tofa further repressed cathelicidin, it prevented the induction of intracellular HAMP and restored the expression of antigen-presentation molecules in toll-like receptor 4-activated macrophages. Our study supports the concept that induction of IL10/IL-10R signaling drives a complex immune evasion strategy of intracellular microbes. Moreover, we conclude that tofa has diverging effects on macrophage host response pathways, and we identify the toll-like receptor 4-IL-10-signal transducer and activator of transcription 3-HAMP axis as a potential therapeutic target to counteract immune evasion.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Knoke, Kristin UNSPECIFIED UNSPECIFIED UNSPECIFIED Rongisch, Robert R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Grzes, Katarzyna M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarz, Roman UNSPECIFIED UNSPECIFIED UNSPECIFIED Lorenz, Beate UNSPECIFIED orcid.org/0000-0001-7880-6272 UNSPECIFIED Yogev, Nir UNSPECIFIED UNSPECIFIED UNSPECIFIED Pearce, Erika L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pearce, Edward J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kofler, David M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fabri, Mario UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-677771
DOI:	10.1016/j.jid.2021.07.180
Journal or Publication Title:	J. Invest. Dermatol.
Volume:	142
Number:	3 PT A
Page Range:	S. 559 - 577
Date:	2022
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1523-1747
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RHEUMATOID-ARTHRITIS; MYCOBACTERIUM-TUBERCULOSIS; ANTIMICROBIAL ACTIVITY; DISEASE PROGRESSION; KINASE INHIBITOR; IRON EFFLUX; IL-10; HEPCIDIN; INTERLEUKIN-10; EXPRESSION Multiple languages Dermatology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67777