title: Serine protease inhibitor, 4-(2-aminoethyl)-benzene sulfonyl fluoride, impairs IL-12-induced activation of pSTAT4β, NFκB, and select pro-inflammatory mediators from estrogen-treated mice.
abstract: Estrogen, a natural immunomodulator, is believed to be involved in the regulation of not only normal immune responses, but also pathological conditions such as inflammatory and autoimmune diseases. We have previously reported that estrogen exposure induces several pro-inflammatory molecules including nitric oxide, cytokines and chemokines (IFNγ, IL-12, MCP-1, etc.) and modifies transcription factors (preferential expression of STAT4β, increased NFκB p50/p50 DNA binding, and enhanced T-bet and Bcl-3) from activated splenocytes. Given that estrogen promotes diverse range of pro-inflammatory molecules, and modifies transcription factors, it is plausible that estrogen upregulates a common set of molecular event(s) that favors inflammation. Serine proteases are thought to play an important role in inflammation. Therefore in this study, we investigated the consequence of exposure of splenocytes stimulated with a key Th1/IFNγ-inducing cytokine IL-12 or ConA from estrogen-treated mice to a serine protease inhibitor, 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), on inflammatory cytokines (IFNγ, IL-12) and related transcription factors (STAT4α/β, T-bet, NFκB). Exposure of splenocytes to AEBSF for 3h noticeably inhibited the induction of IFNγ, IL-12, and IL-12-induced STAT4β, mRNA expression of T-bet and IL-12Rβ2. The AEBSF-mediated inhibition of cytokines was accompanied by the expression of a normal-sized NFκB, downregulation of p50/p50 DNA binding but did not alter Bcl3. These findings provide a new understanding of inflammation and inhibition of serine proteases has important implications for designing novel therapeutic strategies for a broad range of inflammatory diseases.
authors.affiliation: College of Veterinary Medicine, Department of Anatomy and Radiology, University of Georgia, Athens, GA 30621, USA.
authors.forename: Ebru
authors.initials: E
authors.lastname: Karpuzoglu
authors.forename: Robert M
authors.initials: RM
authors.lastname: Gogal
authors.forename: S
authors.initials: S
authors.lastname: Ansar Ahmed
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D007249:Inflammation; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000235:genetics / Q000378:metabolism; D057057:Serine Proteases / Q000276:immunology / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013450:Sulfones / Q000494:pharmacology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D058408:Th1-Th2 Balance / Q000187:drug effects; D000098815:T-bet Transcription Factor
chemical_list: D016207:Cytokines; D004967:Estrogens; C508443:Il12rb2 protein, mouse; D018836:Inflammation Mediators; D016328:NF-kappa B; D053707:Receptors, Interleukin-12; D015842:Serine Proteinase Inhibitors; D013450:Sulfones; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D057057:Serine Proteases