THE INNATE IMMUNE PROTEIN NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN IS INVOLVED IN THE EARLY THERAPEUTIC RESPONSE TO 13-CIS RETINOIC ACID IN ACNE PATIENTS

Open Access
- Author:
- Lumsden, Kimberly Ruth
- Graduate Program:
- Molecular Medicine
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- April 24, 2009
- Committee Members:
- Diane M Thiboutot, Dissertation Advisor/Co-Advisor
Diane M Thiboutot, Committee Chair/Co-Chair
Judith S Bond, Committee Member
Robert Harold Bonneau, Committee Member
Gary Alan Clawson, Committee Member
James Robert Connor, Committee Member - Keywords:
- Neutrophil Gelasinase-Associated Lipocalin
Propionibacterium acnes
Acne - Abstract:
- Acne is a disease that affects approximately 40-50 million Americans at any given time. For those with moderate to severe acne the choice of treatments is limited. The most effective agent for the treatment of acne is isotretinoin (Accutane®, 13-cis Retinoic Acid (RA)). 13-cis RA has teratogenic effects and its use is highly regulated. Although this drug has been used for over 25 years for acne, until recently little was known about its mechanism of action. Recent data indicate that the beneficial effect of isotretinoin in reducing sebum production is mediated by neutrophil gelatinase-associated lipocalin (NGAL). NGAL is a 25 kDa secreted protein with antimicrobial properties which has been reported to affect cell survival. Patients treated with isotretinoin have increased expression of NGAL in their sebaceous glands where it is induces apoptosis leading to reduced production of sebum and improvement in acne. This protein may be an important target for the development of alternate therapies to 13-cis RA. The studies in this thesis indicate that NGAL is an important innate immune protein in the resolution of acne. NGAL’s increase on the skin surface of acne patients compared to the skin from normal volunteers has been identified through IHC and ELISA assays. Sebocytes treated with P. acnes have increased NGAL expression and secretion through a TLR-2 dependent mechanism. This increase in NGAL in acne skin and in sebocytes treated with P. acnes is much smaller than the increase observed with 13-cis RA treatment in patient skin and in cultured sebocytes. It has been determined that NGAL has antibacterial activity against P. acnes. The hypothesis is that the skin secretes NGAL as a response to the acne milieu but the levels are not sufficient to resolve acne. On the contary 13-cis RA increases NGAL to therapeutic levels that contribute to acne resolution. The current in vivo studies have revealed that significantly increased levels of NGAL can be recovered from patient skin as early as 1 week after beginning treatment with 13-cis RA and this increase correlates with a decrease in sebum and P. acnes levels on the skin. It has also been shown that NGAL and sebum levels plateau at approximately 8 weeks of treatment. These data indicate that NGAL is an important early response protein for 13-cis RA mediated acne resolution and may represent a target for the design of therapeutic alternatives to 13-cis RA.