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Effects of protease inhibitors on LPS-mediated activation of a mouse macrophage cell line (J774)

Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, Laboratory of Molecular Virology and Carcinogenesis, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland, USA

Y. Muroi

Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, Laboratory of Molecular Virology and Carcinogenesis, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland, USA

N. Ito

Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, Laboratory of Molecular Virology and Carcinogenesis, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland, USA

N.R. Rice

Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, Laboratory of Molecular Virology and Carcinogenesis, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland, USA

T. Suzuki

Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, Laboratory of Molecular Virology and Carcinogenesis, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland, USA

Pretreatment (1 h) of a mouse macrophage-like cell line, J774, with the protease inhibitor, phenylalanine-chloromethyl ketone (PCK) or its structural analogue, tosylphenylalanine chloromethyl ketone (TPCK) was found to cause substantial inhibition of LPS-triggered activation of NF-B. Pretreatment of cells with other types of protease inhibitors or their various structural analogues had no effect. PCK or TPCK appeared to exert its inhibitory effect by: (i) partially preventing LPS-triggered degradation of IB protein; (ii) preventing LPS-triggered nuclear translocation of NF-B proteins (p50, RelA and Rel); and (iii) inhibiting the DNA-binding activities of NF-B proteins. Pretreatment of cells with PCK or TPCK also resulted in the total or partial inhibition of LPS activatable (AP-1 or CREB) or constitutively-existing (Oct-1) transcription factors, but not of another constitutively-expressed transcription factor (SP-1). Pretreatment of J774 cells with PCK was found to substantially suppress LPS-induced expression of mRNAs specific for cytokine genes (TNF, IL-1 and β, and IL-6), inducible nitric oxide synthase (iNOS) gene and IB gene, but not NF-B1 p105 gene or β-actin gene. Furthermore, PCK pretreatment inhibited, in a dose-dependent manner, LPS-triggered production of nitric oxide production and tumoricidal activity.

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