title: CD40 and tumour necrosis factor-α co-operate to up-regulate inducuble nitric oxide synthase expression in macrophages.
abstract: Regulation of inducible nitric oxide synthase (NOS2) expression is important given the role of this enzyme in inflammation, control of infections and immune regulation. In contrast to tumour necrosis factor-α (TNF-α) alone or CD40 stimulation alone, simultaneous stimulation of mouse macrophages through CD40 ligation and TNF-α led to up-regulation of NOS2 and nitric oxide production. This response was of functional relevance because CD40/TNF-α-stimulated macrophages acquired nitric oxide-dependent anti-Leishmania major activity. CD40 plus TNF-α up-regulated NOS2 independently of interferon-γ, interferon-α/β and interleukin-1. TNF receptor-associated factor 6 (TRAF6), an adapter protein downstream of CD40, appears to be required for NOS2 up-regulation because a CD40-TRAF6 blocking peptide inhibited up-regulation of NOS2 in CD40/TNF-α-stimulated macrophages. CCAAT/enhancer-binding protein-β (C/EBPβ), a transcription factor activated by TNF-α but not CD40, was required for NOS2 up-regulation because this enzyme was not up-regulated when C/EBPβ(-/-)  macrophages received CD40 plus TNF-α stimulation. These results indicate that CD40 and TNF-α co-operate to up-regulate NOS2, probably via the effect of TRAF6 and C/EBPβ.
authors: Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH OH 44106, USA.
authors: Jose-Andres C
authors: JA
authors: Portillo
authors: Luis Muniz
authors: LM
authors: Feliciano
authors: Genevieve
authors: G
authors: Okenka
authors: Frederick
authors: F
authors: Heinzel
authors: M Cecilia
authors: MC
authors: Subauste
authors: Carlos S
authors: CS
authors: Subauste
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000276:immunology*; D018320:Leishmania major / Q000276:immunology / Q000302:isolation & purification; D016773:Leishmaniasis, Cutaneous / Q000276:immunology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000172:deficiency / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000276:immunology*
chemical_list: D019013:CD40 Antigens; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II