Original article
Cathelicidin, kallikrein 5, and serine protease activity is inhibited during treatment of rosacea with azelaic acid 15% gel

https://doi.org/10.1016/j.jaad.2013.05.019Get rights and content

Background

Excess cathelicidin and kallikrein 5 (KLK5) have been hypothesized to play a role in the pathophysiology of rosacea.

Objective

We sought to evaluate the effects of azelaic acid (AzA) on these elements of the innate immune system.

Methods

Gene expression and protease activity were measured in laboratory models and patients with rosacea during a 16-week multicenter, prospective, open-label study of 15% AzA gel.

Results

AzA directly inhibited KLK5 in cultured keratinocytes and gene expression of KLK5, Toll-like receptor-2, and cathelicidin in mouse skin. Patients with rosacea showed reduction in cathelicidin and KLK5 messenger RNA after treatment with AzA gel. Subjects without rosacea had lower serine protease activity (SPA) than patients with rosacea. Distinct subsets of patients with rosacea who had high and low baseline SPA were identified, and patients with high baseline exhibited a statistically significant reduction of SPA with 15% AzA gel treatment.

Limitations

Study size was insufficient to predict clinical efficacy based on the innate immune response to AzA.

Conclusions

These results show that cathelicidin and KLK5 decrease in association with AZA exposure. Our observations suggest a new mechanism of action for AzA and that SPA may be a useful biomarker for disease activity.

Section snippets

Patients

This study was designed as a multicenter study at University of California–San Diego; University of Alabama, Birmingham; and Valley Hospital Medical Center, Las Vegas, NV. After approval by the Human Research Protection Program at the University of California–San Diego (institutional review board reference number 100473), and upon receiving written informed consent before sampling, 60 adult individuals (age 18-80 years) with at least mild rosacea were enrolled and 55 of those completed the

AzA inhibits KLK5 protein expression in cultured human keratinocytes

To evaluate the effects of AzA on the production of KLK5 in cultured keratinocytes, we compared KLK5 messenger RNA (mRNA) and protein expression in normal human epidermal keratinocytes treated for 24 hours with AzA at concentrations of 10−2 to 10−13. Protein expression of KLK5 was inhibited by AzA at concentrations of 10−8 mol/L, but only when keratinocytes were grown in high-calcium concentrations (Fig 1, A). There was also a corresponding decrease in KLK5 mRNA expression as measured by

Discussion

Although the cause of rosacea is a complex combination of environmental and genetic factors, considerable evidence suggests an aberrant innate immune detection and response system is important to its development. Previous studies have shown that facial skin from patients with rosacea has excess expression of genes that increase both the sensitivity and reactivity to a variety of environmental triggers including TLR2, KLK5, and CAMP.17 In this study we evaluated whether AzA, a commonly used

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  • Cited by (0)

    Supported in part by National Institutes of Health grant R01-AR052728 to Dr Gallo and an investigator-initiated grant from Bayer (Intendis) to Drs Gallo, Hata, Del Rosso, and Harper.

    Disclosure: Dr Del Rosso currently serves or has recently (within the last 2 years) served as a consultant, speaker, and/or researcher for Bayer Dermatology. Dr Coda, Dr Miller, Mr Audish, Mr Kotol, Dr Two, Dr Yamasaki, and Dr Shafiq have no conflicts of interest to declare.

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