Zhaoyuan Cong

Systemic Isotretinoin Therapy Normalizes Exaggerated TLR-2-Mediated Innate Immune Responses in Acne Patients

Retinoids are used in the treatment of inflammatory skin diseases and malignancies, but studies characterizing the in vivo actions of these drugs in humans are lacking. Isotretinoin is a pro-drug for all-trans retinoic acid that can induce long-term remissions of acne; however, its complete mechanism of action is unknown. We hypothesized that isotretinoin induces remission of acne by normalizing the innate immune response to the commensal bacterium P. acnes. Compared to normal subjects, peripheral blood monocytes from acne patients expressed significantly higher levels of TLR-2 and exhibited significantly greater induction of TLR-2 expression following P. acnes stimulation. Treatment of patients with isotretinoin significantly decreased monocyte TLR-2 expression and subsequent inflammatory cytokine response to P. acnes by one week of therapy. This effect was sustained six months following cessation of therapy, indicating that TLR-2 modulation may be involved in the durable therapeutic response to isotretinoin. This study demonstrates that isotretinoin exerts immunomodulatory effects in patients and sheds light on a potential mechanism for its long-term effects in acne. The modulation of TLR-2 expression on monocytes has important implications in other inflammatory disorders characterized by TLR-2 dysregulation.

TRAIL contributes to the apoptotic effect of 13-cis retinoic acid in human sebaceous gland cells

Background  The full mechanism of action of isotretinoin [13‐cis retinoic acid (13‐cis RA)] in treating acne is unknown. 13‐cis RA induces key genes in sebocytes that are involved in apoptosis, including Tumor necrosis factor Related Apoptosis Inducing Ligand (TRAIL).

Isotretinoin Increases Skin Surface Levels of Neutrophil Gelatinase-Associated Lipocalin in Patients Treated for Severe Acne

Background  A clear‐cut need exists for safe and effective alternatives to the use of isotretinoin in severe acne. Lack of data regarding the specifics of isotretinoin’s mechanism of action has hampered progress in this area. Recently, the protein neutrophil gelatinase‐associated lipocalin (NGAL) has been identified as a mediator of the apoptotic effect of isotretinoin on sebocytes.

Selective Rho Kinase Inhibitor Allows for Expansion of Human Primary Sebocytes In Vitro

TO THE EDITOR The use of primary human cells for research is hampered by the inability to grow and maintain the substantial amount of cells required for experimental assays. Primary sebocytes (P-Sebs) are especially difficult to grow in culture because of their innate programming that causes the cells to accumulate lipids and undergo holocrine rupture within days of their isolation (Xia et al., 1989). As such, the use of sebocyte cell lines immortalized by SV40 large T antigen or human papilloma virus E6/E7 oncogenes are used to enhance the proliferative capacity of these cells, but immortalization prevents complete differentiation (Lo Celso et al., 2008; Thiboutot et al., 2003; Zouboulis et al., 1999). Y-27632 is a small molecule that, when used at concentrations of less than 10 mM, selectively inhibits both isoforms of Rho-associated protein kinase (ROCK I and II), resulting in blockage of integrin-mediated cell contact inhibition. When used at higher concentrations, Y-27632 will also inhibit protein kinase C, protein kinase A, and myosin light-chain kinases (Narumiya et al., 2000). Y-27632 has been successfully used to expand and maintain the survival of other primary human cells including keratinocytes, fibroblasts, endothelial cells, and adipose-derived stem cells (Chapman et al., 2010; Peh et al., 2015; Piltti et al., 2015; Qu et al., 2014). As previously shown in keratinocytes (Chapman et al., 2014), we describe a method of reversibly immortalizing P-Sebs, allowing for their expansion in culture using 3T3 fibroblast feeder layers and Y-27632 (5 mmol/L).