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Inflammation and Extracellular Matrix Degradation Mediated by Activated Transcription Factors Nuclear Factor-Κb and Activator P

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Inflammation and Extracellular Matrix Degradation Mediated by Activated Transcription Factors Nuclear Factor-Κb and Activator P American Journal of Pathology, Vol. 166, No. 6, June 2005 Copyright © American Society for Investigative Pathology Matrix Pathobiology Inflammation and Extracellular Matrix Degradation Mediated by Activated Transcription Factors Nuclear Factor-␬B and Activator Protein-1 in Inflammatory Acne Lesions in Vivo Sewon Kang, Soyun Cho, Jin Ho Chung, Despite its common occurrence, the pathogenesis of Craig Hammerberg, Gary J. Fisher, and acne is not fully understood. Excessive shedding of ep- John J. Voorhees ithelial cells from the walls of follicles combined with increased amounts of sebum produced by associated From the Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan sebaceous glands are two important factors that contrib- ute to follicular obstruction.4,5 This obstruction leads to the formation of microcomedos, which are believed to be the precursor lesions of acne.5 These microcomedos may evolve into clinically visible comedos (blackheads Acne is the most common skin disease, causing sig- and whiteheads) or inflammatory lesions (papules, pus- nificant psychosocial problems for those afflicted. tules, or cysts). Propionibacterium acnes (P. acnes) are Currently available agents for acne treatment, such as gram-positive, anaerobic diphtheroids that are part of the oral antibiotics and isotretinoin (Accutane), have lim- 6 normal skin flora. In the generation of inflammatory le- ited use. Thus, development of novel agents to treat sions, proliferation of P. acnes in the obstructed follicles is this disease is needed. However, the pathophysiology believed to be critical.6,7 This is based on in vitro data that of acne inflammation is poorly understood. Before P. acnes stimulate monocytes to produce proinflamma- new therapeutic strategies can be devised, knowledge tory mediators and chemotactic factors,7,8 and time- regarding molecular mechanisms of acne inflamma- tested clinical observations that antibiotics that inhibit P. tion is required. We report here that transcription acnes factors nuclear factor-␬B and activator protein-1 are improve inflammatory acne. activated in acne lesions with consequent elevated It is a well established clinical fact that inadequate expression of their target gene products, inflamma- control of acne inflammation can later lead to scarring. tory cytokines and matrix-degrading metalloprotein- Scarring is the most unfortunate and undesirable sequela ases, respectively. These elevated gene products are of acne, because once formed, it is not amenable to molecular mediators of inflammation and collagen pharmacological treatment and requires invasive proce- degradation in acne lesions in vivo. This new knowl- dures such as chemical peels, dermabrasion, or laser 9,10 edge enables a rational strategy for development of resurfacing to improve its appearance. These proce- pharmacological agents that can target the inflamma- dures are not only costly, but they themselves are asso- tion and matrix remodeling that occurs in severe ciated with further risks of scarring and pigmentary ab- acne. (Am J Pathol 2005, 166:1691–1699) Supported in part by the Babcock Endowment for Dermatological Re- 1 Acne vulgaris is a disorder of sebaceous follicles. Found search and the National Institutes of Health (K24 to S.K.). primarily on the face and upper trunk (chest and back), Presented in part at the annual meeting of the Society for Investigative these specialized follicles have prominent sebaceous Dermatology, Los Angeles, CA, May 15 to 18, 2002. glands associated with them. Acne is the most common Accepted for publication February 17, 2005. skin disease, estimated to affect ϳ80% of individuals at Current address of S.C. and J.H.C.: Department of Dermatology, Seoul 2 some point between the ages of 11 and 30 years. Al- National University College of Medicine, Seoul, Korea. though not life-threatening, acne can adversely impact Address reprint requests to Sewon Kang, M.D., Department of Derma- psychosocial development, and may cause significant tology, University of Michigan Medical Center, 1910 Taubman Center, emotional problems, depression, and even suicide.3 Ann Arbor, MI 48109. E-mail: [email protected]. 1691 1692 Kang et al AJP June 2005, Vol. 166, No. 6 normalities. Thus, preventing scar formation is a major plied Biosystems) and a 7700 sequence detector system goal in the treatment of inflammatory acne. (Applied Biosystems). Thus, one 3-mm punch biopsy was Currently, inflammatory acne is treated with antibiotics sufficient to quantify expression of at least 100 genes. All (both oral and topical) or oral isotretinoin (Accutane). liquid handling procedures were performed with a cali- Although widely used and often effective, antibiotics have brated robotic workstation (Biomek 2000; Beckman Coulter, a significant limitation, which is development of resistant Inc., Hialeah, FL) to ensure accuracy and reproducibility. strains of P. acnes.11–13 Oral isotretinoin is by far the most Target gene mRNA levels (number of molecules/10 ng total effective treatment for severe inflammatory acne, rou- RNA) were quantified based on a standard curve and nor- tinely delivering dramatic improvements.14,15 However, malized to 36B4 mRNA levels. PCR primers and probes for because of its established teratogenicity, isotretinoin use MMP-1, MMP-3, MMP-9, procollagen I, procollagen III, and has been restricted. Furthermore, the recently publicized, 36B4 (control gene) were produced by a custom oligonu- controversial risk of depression/suicidal ideation has cleotide synthesis service (Applied Biosystems). Cycle 16,17 made isotretinoin use even more problematic. There- threshold (CT)valuesforgenesofinterestrangedfromϳ22 fore, current treatment options for inflammatory acne are to 28. CT value for 36B4 was ϳ20. Duplicate CT values did suboptimum. Rational development of new treatments for not vary by more than 3%, and were well within the linear acne necessitates a molecular description of mecha- range of quantitation, based on standard curves. nisms involved in acne inflammation in vivo because no animal model exists. Here we describe the key inflamma- tory signaling pathways that are activated in facial acne Measurement of Cytokine mRNA Levels lesions from human patients. mRNA levels of 12 different cytokines [interleukin (IL)-1␣, IL-1␤,IL-2,IL-4,IL-5,IL-8,IL-10,IL-12p35,IL12p40,IL-15, Materials and Methods interferon (IFN)-␥,andtumornecrosisfactor(TNF)-␣]were measured using the TaqMan Cytokine Gene Expression Tissue Samples Plate I kit (Applied Biosystems). Reverse transcriptase (RT)- PCR was performed with 18s-rRNA as endogenous control, We studied skin samples from 16 patients (4 men and 12 and the data were analyzed using a 7700 sequence detec- women; mean age, 25 years; range, 13 to 39 years) with tor system (Applied Biosystems). inflammatory acne. Before skin biopsy, patients must not have used any systemic (4 weeks) or topical (2 weeks) acne medications. Skin of one to two inflammatory lesions Western Analysis of MMP-8 Protein (red raised papules, n ϭ 16, or pustules, n ϭ 2, with a ring of erythema) and an adjacent, uninvolved normal area In three patients, MMP-8 protein levels in supernatants from was obtained from the face of each patient using a 3-mm skin homogenates were determined by Western blot anal- punch biopsy instrument. Routinely used in dermatology, ysis, as previously described.18 Rabbit polyclonal MMP-8 3-mm punch cleanly cuts a cylindrical core of epidermis, antibody (Chemicon, Temecula, CA) was used. Equal dermis, and subcutis (fat). After the plug of tissue is amounts of protein (100 ␮g/lane) were analyzed for each removed, 5-0 prolene suture is placed to close the circu- sample from an acne lesion and uninvolved adjacent skin. lar opening. Seven days after the procedure, the suture is removed. A 3-mm linear scar is formed, but it blends well with the surrounding skin and becomes difficult to appre- Immunohistology ciate, especially on the face. The skin specimens were For immunohistological analysis, 6-␮mskincryosections OCT-embedded for immunohistological analysis and in were air-dried and fixed in paraformaldehyde and pro- situ zymography, and snap-frozen for all other assays. cessed as previously described.18 Slides were incubated The study was approved by the institutional review board (1 hour) with mouse monoclonal antibodies for c-Jun (1:200; at the University of Michigan, and all patients provided Transduction Laboratories, Lexington, KY), MMP-1 (1:250, written informed consent before entering the study. Chemicon), MMP-3 (1:50, Chemicon), MMP-9 (1:50, Chemi- con), or procollagen I [SP1.D8 developed by Dr. Heniz Measurement of Matrix Metalloproteinase Furthmayer and obtained from the Developmental Studies (MMP) and Procollagen mRNA Levels Hybridoma Bank developed under the auspices of the Na- tional Institute of Child Health and Human Development and Total RNA was extracted using a commercial kit (RNeasy maintained by the University of Iowa, Department of Biolog- Mini kit; Qiagen, Chatsworth, CA). One 3-mm punch biopsy ical Sciences, Iowa City, IA; and PIC, a mouse monoclonal of acne lesion or normal face typically yielded ϳ1 ␮goftotal antibody (clone PC8-7, IgG1) obtained from PanVera Corp. RNA. cDNA synthesis was performed with 0.1 ␮goftotal (Madison, WI), which detects procollagen type I C-terminal RNA, in a volume of 50 ␮l. Reverse transcription was per- peptide antibodies]. Sections were then incubated with a formed using a TaqMan reverse transcription kit (Applied biotinylated
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