Isotretinoin treatment upregulates the expression of p53 in the skin and sebaceous glands of patients with acne vulgaris

Abstract

The transcriptomic regulation induced by isotretinoin (13-cis retinoic acid) is still a matter of debate as short-term exposures of immortalized sebocytes with isotretinoin produced conflicting results. Based on translational evidence, it has been hypothesized that oral isotretinoin treatment upregulates the expression of the transcription factor p53. Twenty-five patients suffering from acne vulgaris were treated with isotretinoin (0.6 mg/kg body weight) for 6 weeks. Biopsies from back skin were taken before and after isotretinoin treatment for the determination of p53 expression by immunohistochemical staining, quantification of p53 protein concentration by enzyme-linked immunosorbent assay and TP53 gene expression by quantitative reverse transcription real time PCR. Fifteen socio-demographically cross-matched healthy volunteers served as controls. Isotretinoin treatment significantly increased the nuclear expression of p53 in sebaceous glands of treated patients compared to pre-treatment levels and p53 levels of untreated controls. Furthermore, the p53 protein and gene expression significantly increased in the skin after treatment. The magnitude of p53 expression showed an inverse correlation to acne severity score and body mass index. Under clinical conditions, isotretinoin induced the expression of p53, which controls multiple transcription factors involved in the pathogenesis of acne vulgaris including FoxO1, androgen receptor and critical genes involved in the induction of autophagy and apoptosis. Increased p53-FoxO1 signalling enhanced by systemic isotretinoin treatment explains the underlying transcriptomic changes causing sebum suppression but also the adverse effects associated with systemic isotretinoin therapy.

Keywords: Acne; Gene expression; Isotretinoin; Sebaceous gland; p53.

Fig. 1

Immune staining of nuclear p53 before and after isotretinoin treatment. a p53 nuclear immune staining in sebaceous gland of acne patient before isotretinoin therapy. b Intensified nuclear p53 immune staining after 6 weeks of isotretinoin therapy

Fig. 2

p53 protein and gene expression before and after isotretinoin therapy. a Illustrates the changes of p53 protein and b the changes of p53 gene expression of back skin biopsies of acne patients before and after 6 weeks of oral isotretinoin treatment compared to acne-free control skin biopsies

Fig. 3

Correlation between p53 protein and gene expression with acne severity grade. a Shows a negative correlation between p53 protein expression and b an inverse relation between p53 gene expression with acne severity grade

Fig. 4

a Correlation between BMI and protein expression by ELISA in cases group (n = 50) b correlation between BMI and gene expression of p53 by RT-PCR in cases group (n = 50)