TLR Stimulation Produces IFN-β as the Primary Driver of IFN Signaling in Nonlymphoid Primary Human Cells.

Autor:	Nistler R; Centers for Therapeutic Innovation, Pfizer Inc., Cambridge, MA 02139., Sharma A; Centers for Therapeutic Innovation, Pfizer Inc., Cambridge, MA 02139., Meeth K; Centers for Therapeutic Innovation, Pfizer Inc., Cambridge, MA 02139., Huard C; Centers for Therapeutic Innovation, Pfizer Inc., Cambridge, MA 02139., Loreth C; Research Business Technology, Pfizer Inc., Cambridge, MA 02139., Kalbasi A; Centers for Therapeutic Innovation, Pfizer Inc., Cambridge, MA 02139., Tyminski E; Centers for Therapeutic Innovation, Pfizer Inc., Cambridge, MA 02139., Bellmore R; Research Business Technology, Pfizer Inc., Cambridge, MA 02139., Coyle AJ; Centers for Therapeutic Innovation, Pfizer Inc., Cambridge, MA 02139., Gullà SV; Centers for Therapeutic Innovation, Pfizer Inc., Cambridge, MA 02139., Berasi SP; Centers for Therapeutic Innovation, Pfizer Inc., Cambridge, MA 02139., Greenberg SA; Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115; and sagreenberg@partners.org janet.buhlmann@pfizer.com.; Boston Children's Hospital Computational Health Informatics Program, Harvard Medical School, Boston, MA 02115., Buhlmann JE; Centers for Therapeutic Innovation, Pfizer Inc., Cambridge, MA 02139; sagreenberg@partners.org janet.buhlmann@pfizer.com.
Jazyk:	angličtina
Zdroj:	ImmunoHorizons [Immunohorizons] 2020 Jun 18; Vol. 4 (6), pp. 332-338. Date of Electronic Publication: 2020 Jun 18.
DOI:	10.4049/immunohorizons.1800054
Abstrakt:	Several human autoimmune diseases are characterized by increased expression of type 1 IFN-stimulated genes in both the peripheral blood and tissue. The contributions of different type I IFNs to this gene signature are uncertain as the type I IFN family consists of 13 alphas and one each of β, ε, κ, and ω subtypes. We sought to investigate the contribution of various IFNs to IFN signaling in primary human cell types. We stimulated primary skin, muscle, kidney, and PBMCs from normal healthy human donors with various TLR ligands and measured the expression of type I IFN subtypes and activation of downstream signaling by quantitative PCR. We show that IFNB1 is the dominant type I IFN expressed upon TLR3 and TLR4 stimulation, and its expression profile is associated with subsequent MX1 transcription. Furthermore, using an IFN-β-specific neutralizing Ab, we show that MX1 expression is inhibited in a dose-dependent manner, suggesting that IFN-β is the primary driver of IFN-stimulated genes following TLR3 and TLR4 engagement. Stimulation with TLR7/8 and TLR9 ligands induced IFNB1 and IFNA subtypes and MX1 expression only in PBMCs and not in tissue resident cell types. Concordantly, IFN-β neutralization had no effect on MX1 expression in PBMCs potentially because of the combination of IFNB1 and IFNA expression. Combined, these data highlight the potential role for IFN-β in driving local inflammatory responses in clinically relevant human tissue types and opportunities to treat local inflammation by targeting IFN-β. (Copyright © 2020 The Authors.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu