Insights into the Mechanism of Action of 13-cis Retinoic Acid in Suppressing Sebaceous Gland Function
Open Access
- Author:
- Nelson, Amanda Marie
- Graduate Program:
- Molecular Medicine
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- February 26, 2007
- Committee Members:
- Diane M Thiboutot, Committee Chair/Co-Chair
Gary Alan Clawson, Committee Member
Mark Kester, Ph D, Committee Member
Jeffrey Maurice Peters, Committee Member
Jong Kak Yun, Committee Member - Keywords:
- skin
retinoin
acne - Abstract:
- Nearly 40-50 million people of all races and ages in the United States have acne, making it the most common skin disease. Although acne is not a serious health threat, severe acne can lead to disfiguring, permanent scarring; increased anxiety; and depression. Isotretinoin (13-cis Retinoic Acid) is the most potent agent that affects each of the pathogenic features of acne: 1) follicular hyperkeratinization, 2) the activity of Propionibacterium acnes, 3) inflammation and 4) increased sebum production. Isotretinoin has been on the market since 1982 and even though it has been prescribed for 25 years, extensive studies into its molecular mechanism of action in human skin and sebaceous glands have not been done. Since isotretinoin is a teratogen, there is a clear need for safe and effective alternative therapeutic agents. The studies undertaken in this thesis were designed to increase our understanding of the effects of 13-cis RA on the sebaceous gland and its mechanism of action in sebum suppression. It is well established that isotretinoin drastically reduces the size and lipid secretion of sebaceous glands. We hypothesized that isotretinoin decreases the size of the sebaceous gland by inducing cell cycle arrest and/or apoptosis and that sebum suppression is most likely an indirect result of the reduced size of the sebaceous gland. Our studies show that 13-cis RA, unlike 9-cis RA or ATRA, induces cell cycle arrest and apoptosis in SEB-1 sebocytes. Its ability to induce apoptosis is not inhibited in the presence of functional retinoic acid receptor (RAR) pan antagonist AGN 193198, suggesting an RAR-independent mechanism of apoptosis. Gene expression analysis was performed in cultured SEB-1 sebocytes that were treated with 13-cis RA and in biopsies of skin taken from patients that were treated for one week with isotretinoin. These data indicate that 13-cis RA increases expression of neutrophil gelatinase associated lipocalin (NGAL) and Tumor Necrosis Factor related apoptosis inducing ligand (TRAIL). In turn, we report that both NGAL and TRAIL induce apoptosis within SEB-1 sebocytes and, as such, are potential mediators of 13-cis RA induced apoptosis in human sebocytes. These studies into the mechanism of action of 13-cis RA in sebaceous glands suggest that 13-cis RA mediates its sebosuppressive effect through preferential induction of apoptosis in sebaceous glands. Furthermore, these data provide a rationale for drug discovery of alternative agents that are capable of selectively inducing apoptosis in sebaceous glands as a treatment for severe acne.