title: TNF receptor-associated factor 6-dependent CD40 signaling primes macrophages to acquire antimicrobial activity in response to TNF-alpha.
abstract: IFN-gamma is considered an essential stimulus that allows macrophages to acquire activity against intracellular pathogens in response to a second signal such as TNF-alpha. However, protection against important pathogens can take place in the absence of IFN-gamma through mechanisms that are still dependent on TNF-alpha. Engagement of CD40 modulates antimicrobial activity in macrophages. However, it is not known whether CD40 can replace IFN-gamma as priming signal for induction of this response. We show that CD40 primes mouse macrophages to acquire antimicrobial activity in response to TNF-alpha. The effect of CD40 was not caused by modulation of IL-10 and TGF-beta production or TNFR expression and did not require IFN-alphabeta signaling. Induction of antimicrobial activity required cooperation between TNFR-associated factor 6-dependent CD40 signaling and TNFR2. These results support a paradigm where TNFR-associated factor 6 signaling downstream of CD40 alters the pattern of response of macrophages to TNF-alpha leading to induction of antimicrobial activity.
authors.affiliation: Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Andrade
authors.forename: Matthew
authors.initials: M
authors.lastname: Wessendarp
authors.forename: Jose-Andres C
authors.initials: JA
authors.lastname: Portillo
authors.forename: Jun-Qi
authors.initials: JQ
authors.lastname: Yang
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Gomez
authors.forename: Joan E
authors.initials: JE
authors.lastname: Durbin
authors.forename: Gail A
authors.initials: GA
authors.lastname: Bishop
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Subauste
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand / Q000494:pharmacology; D005260:Female; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D019013:CD40 Antigens; D047889:Receptors, Tumor Necrosis Factor, Type II; D048029:TNF Receptor-Associated Factor 6; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D007371:Interferon-gamma