Tetracyclines Modulate Protease-Activated Receptor 2-Mediated Proinflammatory Reactions in Epidermal Keratinocytes

Abstract

In addition to their antibiotic effects, tetracyclines have anti-inflammatory action that is often beneficial in the control of inflammatory skin disorders. In this study, we examined the effects of tetracycline (TET) and two of its derivatives, doxycycline (DOX) and minocycline (MIN), on the production of interleukin-8 (IL-8) elicited by the activation of protease-activated receptor 2 (PAR2) in normal human epidermal keratinocytes (NHEK). In NHEK, the production of IL-8 stimulated by an agonist peptide of PAR2, SLIGKIV-NH 2 , at 100 M was significantly reduced by TET, DOX, or MIN at 5 and 10 M, concentrations that are noncytotoxic. The tumor necrosis factor alpha (TNF-␣)-induced production of IL-8 was synergistically augmented by SLIGKIV-NH 2 , and that synergistic increase in the production of IL-8 was suppressed by 100 nM PAR2-specific small interfering RNA. It was also suppressed by TET, DOX, or MIN but not by the 14-membered-ring macrolide antibiotics erythromycin, roxithromycin, and clarithromycin, which also have anti-inflammatory activities, at 10 M. These results suggest that tetracyclines attenuate the PAR2-IL-8 axis in keratinocytes and thereby effectively modulate proinflammatory responses in the skin.

Evaluation of drug and sunscreen permeation via skin irradiated with UVA and UVB: Comparisons of normal skin and chronologically aged skin

“…This may have contributed to the increased skin permeation of tetracycline. This antibiotic drug possesses anti-inflammatory activity with various skin disorders [45]. Drugs that reveal excessive hydrophilicity such as tetracycline (log P = À2.6) have no optimal transport route into the skin, and the SC is the predominant barrier.…”

Alopecic and Aseptic Nodules of the Scalp (Pseudocyst of the Scalp): A Prospective Clinicopathological Study of 15 Cases

“…It also inhibits apoptosis and oxygen species release, and decreases neutrophil migration [7]. Furthermore, doxycycline attenuates the protease-activated receptor 2/interleukin 8 axis in keratinocytes and thereby effectively modulates the pro-inflammatory response in the skin [8]. Other therapeutical options include repetitive punctures [5], local injection of steroids [1,4] and surgical excision [2].…”

Minocycline: far beyond an antibiotic

“…Ishikawa et al (2009) reported that minocycline, at concentrations similar to those obtained therapeutically in serum (5 or 10 mM) (Agwuh and MacGowan, 2006), reduced the protease-activated receptor 2-mediated production of IL-8, and thus attenuated the proinflammatory process in epidermal keratinocytes. They proposed that the ability of tetracyclines to chelate Ca 2+ may contribute to these effects, as protease-activated receptor 2 activation transiently increases intracellular Ca 2+ levels in keratinocytes, triggering the downstream binding of NF-kB to DNA (Macfarlane et al, 2005;Stefansson et al, 2008).…”