Tetracyclines inhibit nitrosothiol production by cytokine-stimulated osteoarthritic synovial cells

Borderie, Didier; Hernvann, Alain; Hilliquin, P.; Lemarchal, H.; Kahan, André; Ekindjian, Ohvanesse G.

doi:10.1007/pl00000263

Cited by 15 publications

(12 citation statements)

References 30 publications

(30 reference statements)

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“…Tetracycline and similar antibiotics such as doxycycline have long been known to effectively decrease inflammation in rheumatoid arthritis (34,35). The present results support the possibility that doxycycline may have potential as an anti-inflammatory treatment for inflammatory lung diseases such as asthma, diffuse panbronchiolitis, chronic bronchitis, and bronchiectasis.…”

Section: Discussionsupporting

confidence: 77%

Doxycycline Modulates Nitric Oxide Production in Murine Lung Epithelial Cells

Hoyt

Ballering

Numanami

et al. 2006

The Journal of Immunology

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Many effective therapeutic agents exhibit effects that are different from their intended primary mode of action. Antibiotics such as doxycycline and erythromycin A are no exception. They also display anti-inflammatory activity. Using LA4 murine lung alveolar epithelial cells, effects of doxycycline and erythromycin A on inducible NO synthase (iNOS) NO production as well as iNOS protein and mRNA production were investigated. Induction of iNOS was accomplished by treatment with cytomix (TNF-α, IL-1β, and IFN-γ each at 5 ng/ml). Production of NO or iNOS was not detected in controls with or without erythromycin A. In the presence of cytomix, erythromycin A did not decrease NO, nitrite, iNOS protein, or mRNA production. In contrast, doxycycline caused a dose-dependent decrease in NO, nitrite, iNOS protein, and mRNA production in cytomix-treated cells. Doxycycline at 30 μg/ml produced a 90% decrease in nitrite and NO production and a 52% decrease in iNOS mRNA transcription compared with cytomix treatment alone. Actinomycin D treatment suggests that doxycycline decreases stability of iNOS mRNA in cytomix-treated cells. To determine a mechanism for the decrease in iNOS expression, NF-κB and AP-1 transcription regulatory systems and p38 MAPK were examined. Doxycycline treatment gave no statistically significant change in NF-κB activation but did decrease p38 MAPK protein in cytomix-treated cells by 50%, suggesting that p38 MAPK may be responsible for stabilization of iNOS mRNA. These results demonstrate that doxycycline decreases NO production from iNOS by destabilization of iNOS mRNA via decreased expression of p38 MAPK.

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Section: Discussionsupporting

confidence: 77%

Doxycycline Modulates Nitric Oxide Production in Murine Lung Epithelial Cells

Hoyt

Ballering

Numanami

et al. 2006

The Journal of Immunology

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“…Minocycline likely modulates one or more of these interactions. Many of these associations have been identified as dependent upon redox status, and in this regard an interesting observation of minocycline is its potential to act as an anti-oxidant in the presence of multiple different reactive oxygen and nitrogen species (Borderie et al , 2001; Kraus et al , 2005; Morimoto et al , 2005; Whiteman and Halliwell, 1997). While the specific mechanism remains to be defined, the previously unexamined suppression of ASK1 activation nevertheless represents an intriguing potential therapeutic target, and places SIV CNS disease with the growing number of neurological diseases in which ASK1 is suggested to play a pathological role (Akterin et al , 2006; Kadowaki et al , 2005; Ouyang and Shen, 2006; Sekine et al , 2006).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of minocycline-induced suppression of simian immunodeficiency virus encephalitis: inhibition of apoptosis signal-regulating kinase 1

2008

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Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) can lead to cognitive dysfunction, even in individuals treated with highly active antiretroviral therapy. Using an established simian immunodeficiency virus (SIV)/macaque model of HIV CNS disease, we previously reported that infection shifts the balance of activation of mitogen-activated protein kinase (MAPK) signaling pathways in the brain, resulting in increased activation of the neurodegenerative MAPKs p38 and JNK. Minocycline treatment of SIV-infected macaques reduced the incidence and severity of SIV encephalitis in this model, and suppressed the activation of p38 in the brain. The purpose of this study was to further examine the effects of minocycline on neurodegenerative MAPK signaling. We first demonstrated that minocycline also decreases JNK activation in the brain and levels of the inflammatory mediator nitric oxide (NO). We next used NO to activate these MAPK pathways in vitro, and demonstrated that minocycline suppresses p38 and JNK activation by reducing intracellular levels, and hence, activation of apoptosis signal-regulating kinase 1 (ASK1), a MAPKKK capable of selectively activating both pathways. We then demonstrated that ASK1 activation in the brain during SIV infection is suppressed by minocycline. By suppressing p38 and JNK activation pathways, which are important for the production of and responses to inflammatory mediators, minocycline may interrupt the vicious cycle of inflammation that both results from, and promotes, virus replication in SIV and HIV CNS disease.

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“…The levels of the two oxidative products of NO metabolism, nitrites, and nitrates were found to be higher in ob/ob livers than in lean littermates, confirming NOS induction in ob/ob livers. 32,33 In contrast, nitrosothiols, a combination of NO with thiol (SH) groups, 34 are significantly reduced in livers from ob/ob animals despite the increased production of NO. Indeed, the formation of nitrosothiols does not depend only on the availability of NO, but also on the degree of oxidative stress affecting the steady-state concentration of SH radicals, as exemplified by the increase in nitrosothiol concentration in fibroblasts treated with SOD.…”

Section: Discussionmentioning

confidence: 99%

Pivotal role of superoxide anion and beneficial effect of antioxidant molecules in murine steatohepatitis

et al. 2004

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Nonalcoholic fatty liver disease, frequently associated with obesity, can lead to nonalcoholic steatohepatitis (NASH) and cirrhosis. The pathophysiology of NASH is poorly understood, and no effective treatment is available. In view of a potential deleterious role for reactive oxygen species (ROS), we investigated the origin of ROS overproduction in NASH. Mitochondrial production of ROS and its alterations in the presence of antioxidant molecules were studied in livers from ob/ob mice that bear a mutation of the leptin gene and develop experimental NASH. N-acetyl-cysteine and the superoxide dismutase (SOD) mimics ambroxol, manganese [III] tetrakis (5,10,15,20 benzoic acid) (MnTBAP), and copper [II] diisopropyl salicylate (CuDIPS) were used to target different checkpoints of the oxidative cascade to determine the pathways involved in ROS production. Liver mitochondria from ob/ob mice generated more O 2°؊ than those of lean littermates (P < .01). Ex vivo, all three SOD mimics decreased O 2°؊ generation (P < .001) and totally inhibited lipid peroxidation (P < .001) versus untreated ob/ob mice. Those modifications were associated with in vivo improvements: MnTBAP and CuDIPS reduced weight (P < .02) and limited the extension of histological liver steatosis by 30% and 52%, respectively, versus untreated ob/ob mice. In conclusion, these data demonstrate deleterious effects of superoxide anions in NASH and point at the potential interest of nonpeptidyl mimics of SOD in the treatment of NASH in

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Tetracyclines inhibit nitrosothiol production by cytokine-stimulated osteoarthritic synovial cells

Abstract: This study provides new information on the mechanism by which tetracyclines exert anti-inflammatory effects, via inhibiting nitrosothiols.

Cited by 15 publications

References 30 publications

Doxycycline Modulates Nitric Oxide Production in Murine Lung Epithelial Cells

Doxycycline Modulates Nitric Oxide Production in Murine Lung Epithelial Cells

Mechanisms of minocycline-induced suppression of simian immunodeficiency virus encephalitis: inhibition of apoptosis signal-regulating kinase 1

Pivotal role of superoxide anion and beneficial effect of antioxidant molecules in murine steatohepatitis

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