Abstract
Doxycycline is used to treat infective diseases because of its broadspectrum efficacy. High dose administration (100 or 200 mg/day) is often responsible for development of bacterial resistances and endogenous flora alterations, whereas low doses (20–40 mg/day) do not alter bacteria susceptibility to antibiotics and exert anti-inflammatory activities. In this study, we wanted to assess the efficacy of both low and high doxycycline doses in modulating IL-8, TNF-α, and IL-6 gene expression in HaCaT cells stimulated with LPS. Three experimental settings were used, differing in the timing of doxycycline treatment in respect to the insult induced by LPS: pretreatment, concomitant, and posttreatment. Low doses were more effective than high doses in modulating gene expression of LPS-induced proinflammatory cytokines (IL-8, TNF-α, and IL-6), when added before (pretreatment) or after (posttreatment) LPS stimulation. This effect was not appreciated when LPS and doxycycline were simultaneously added to cell cultures: in this case high doses were more effective. In conclusion, our in vitro study suggests that low doxycycline doses could be safely used in chronic or acute skin diseases in which the inflammatory process, either constantly in progress or periodically recurring, has to be prevented or controlled.
Highlights
Tetracyclines are a broad-spectrum antibiotics family active against a wide range of microorganisms including grampositive and gram-negative bacteria, Chlamydiae, mycoplasmas, rickettsiae, and protozoan parasites [1, 2]
Low doxycycline doses were more effective than high doses in modulating gene expression of LPS-induced proinflammatory cytokines (IL-8, TNF-α, and IL-6) when added before or after LPS stimulation (Figures 3–5, panels (a) and (c))
Using immortalized keratinocytes stimulated with LPS, we provided evidence that both low and high doxycycline doses were able to modulate the expression of inflammatory mediators, in accordance with previous studies illustrating the capability of both anti-inflammatory and antimicrobial doses to be effective in rosacea treatment [16]
Summary
Tetracyclines are a broad-spectrum antibiotics family active against a wide range of microorganisms including grampositive and gram-negative bacteria, Chlamydiae, mycoplasmas, rickettsiae, and protozoan parasites [1, 2]. Compared with the original tetracycline, the synthetics, including minocycline and doxycycline, show a better pharmacokinetic profile than the first-generation tetracyclines when used orally, being rapidly and completely absorbed, even in elderly populations, with a longer half-life and excellent tissue penetration, with almost complete bioavailability [4, 5]. In addition to their well-characterized antibiotic effects, criticized in recent decades for the emergence of bacterial resistance [6], extensive research on tetracyclines has revealed a range of vastly important pharmacological properties [7] focused on the regulatory influence on the immune system and inflammatory pathway. Tetracyclines inhibit metalloproteinases (MMPs) and suppress hydrolases such as α-amylases and phospholipase A2
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