Macrophage TNF mRNA Expression Is Modulated by Protease Inhibitors

Lo, Chang-fa; Fu, Minjuan; Kim, Barbara

doi:10.1006/jsre.1997.5103

Cited by 20 publications

(14 citation statements)

References 7 publications

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“…This concentration of inhibitor was able to inhibit ϳ80% of the IL-8 produced in both low dose and positive control samples. TNF-␣ production was completely inhibited by TPCK pretreatment (data not shown), as has been demonstrated previously (33,34). These experiments demonstrate that inhibition of NF-B almost completely inhibits the IL-8 production resulting from gonococcal challenge.…”

Section: Effects Of the Nf-b Inhibitor Tpck On Il-8 Productionsupporting

confidence: 88%

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TNF-α-Independent IL-8 Expression: Alterations in Bacterial Challenge Dose Cause Differential Human Monocytic Cytokine Response

Patrone

Bish

Stein

2006

The Journal of Immunology

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We examined the effects of different bacterial doses of Neisseria gonorrhoeae on the cytokine response of primary human monocytes. The data indicate that a low multiplicity of infection (MOI) challenge (MOI = 0.1) results in substantial production of IL-8 and other chemokines/cytokines, in the absence of significant TNF-α production. Positive control challenges (MOI = 10) induced levels of IL-8 that were comparable to the low MOI challenges, but now induced significant levels of TNF-α. Induction of IL-8 expression in low MOI challenges was not mediated by an autocrine response as pretreatment of monocytes with neutralizing Abs against TNF-α or IL-1β had no effect on IL-8 expression. IL-8 induction resulting from gonococcal challenge was shown to require NF-κB activation, though this activation was limited by the inoculating dose. These data indicate that IL-8 induction results from direct contact between bacteria and monocytes. Analysis of the overall cytokine profile revealed patterns of expression for growth-regulated oncogene, MCP-1, and IL-6 that were similar to IL-8. Analysis of various MAPKs indicated that low MOI challenges were able to efficiently activate both the ERK and p38 pathways, but in contrast to positive control samples, failed to activate the JNK pathway. A lack of phosphorylated JNK leads to decreased production of AP-1 dimers, transcription factors that are critical for efficient transcription of TNF-α. Therefore, we propose a mechanism where a low MOI gonococcal challenge results in diminished AP-1 activity and TNF-α production while IL-8 levels remain constant.

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Section: Effects Of the Nf-b Inhibitor Tpck On Il-8 Productionsupporting

confidence: 88%

“…Though the NF-B inhibitor TPCK resulted in complete inhibition of TNF-␣ production, we feel that this is due to TPCK-induced inhibition of TNF-␣ mRNA expression. This effect by TPCK has been previously documented in a model of LPS-stimulated macrophages (33,34).…”

Section: Figuresupporting

confidence: 63%

TNF-α-Independent IL-8 Expression: Alterations in Bacterial Challenge Dose Cause Differential Human Monocytic Cytokine Response

Patrone

Bish

Stein

2006

The Journal of Immunology

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“…et al, 1977). Serine protease inhibitors, such as N-tosyl-Lphenylalanine chloromethyl ketone and N-benzoyl-L-tyrosine ethyl ester, prevented TNF-␣ production and TNF-␣ mRNA expression of macrophages induced by LPS by inhibiting NF-B activity (Lo et al, 1997). Furthermore, Aosasa et al (2001) showed that gabexate mesilate inhibited monocytic TNF-␣ production by inhibiting LPS-induced NF-B activation.…”

Section: Discussionmentioning

confidence: 99%

Gabexate Mesilate, a Synthetic Protease Inhibitor, Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production by Inhibiting Activation of Both Nuclear Factor-κB and Activator Protein-1 in Human Monocytes

Yüksel¹,

Okajima²,

Uchiba³

et al. 2003

J Pharmacol Exp Ther

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Gabexate mesilate, a synthetic protease inhibitor, was shown to be effective in treating patients with sepsis-associated disseminated intravascular coagulation in which tumor necrosis factor-␣ (TNF-␣) plays a critical role. We demonstrated that gabexate mesilate reduced lipopolysaccharide (LPS)-induced tissue injury by inhibiting TNF-␣ production in rats. In the present study, we analyzed the mechanism(s) by which gabexate mesilate inhibits LPS-induced TNF-␣ production in human monocytes in vitro. Gabexate mesilate inhibited the production of TNF-␣ in monocytes stimulated with LPS. Gabexate mesilate inhibited both the binding of nuclear factor-B (NF-B) to target sites and the degradation of inhibitory B␣. Gabexate mesilate also inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase pathways. These observations strongly suggest that gabexate mesilate inhibited LPS-induced TNF-␣ production in human monocytes by inhibiting activation of both NF-B and AP-1. Inhibition of TNF-␣ production by gabexate mesilate might explain at least partly its therapeutic effects in animals given LPS and those in patients with sepsis.

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“…Mf TNF production was measured using the biologic cytotoxicity by LPS-Stimulated Mf assay with transformed mouse fibroblasts (NCTC clone L929 American Type Culture Collection) as previously described [27]. L929 cells…”

Section: Assays For Tnf Effect Of Iloprost On the Tnf Productionmentioning

confidence: 99%

Prostaglandin I2Analogue, Iloprost, Down Regulates Mitogen-Activated Protein Kinases of Macrophages

1998

Journal of Surgical Research

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Macrophage TNF mRNA Expression Is Modulated by Protease Inhibitors

Cited by 20 publications

References 7 publications

TNF-α-Independent IL-8 Expression: Alterations in Bacterial Challenge Dose Cause Differential Human Monocytic Cytokine Response

TNF-α-Independent IL-8 Expression: Alterations in Bacterial Challenge Dose Cause Differential Human Monocytic Cytokine Response

Gabexate Mesilate, a Synthetic Protease Inhibitor, Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production by Inhibiting Activation of Both Nuclear Factor-κB and Activator Protein-1 in Human Monocytes

Prostaglandin I2Analogue, Iloprost, Down Regulates Mitogen-Activated Protein Kinases of Macrophages

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