Acne is the most common skin disease, causing significant psychosocial problems for those afflicted. Currently available agents for acne treatment, such as oral antibiotics and isotretinoin (Accutane), have limited use. Thus, development of novel agents to treat this disease is needed. However, the pathophysiology of acne inflammation is poorly understood. Before new therapeutic strategies can be devised, knowledge regarding molecular mechanisms of acne inflammation is required. We report here that transcription factors nuclear factor-kappaB and activator protein-1 are activated in acne lesions with consequent elevated expression of their target gene products, inflammatory cytokines and matrix-degrading metalloproteinases, respectively. These elevated gene products are molecular mediators of inflammation and collagen degradation in acne lesions in vivo. This new knowledge enables a rational strategy for development of pharmacological agents that can target the inflammation and matrix remodeling that occurs in severe acne.

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A cDNA encoding a receptor antagonist of interleukin 1 (IL-ira), secreted from human monocytes, has recently been isolated and sequenced

An early cellular event in the development of psoriatic lesions is the infiltration of the target tissue by macrophages and activated T lymphocytes (8-10). Lesional psoriatic skin contains activated memory T lymphocytes ( 10-15 ) whose production of mRNA for lymphokines such as IL-2, y-IFN, and TNF-a is elevated relative to normal or uninvolved psoriatic epidermis (16). That the T cell activation and soluble lymphokine production plays a crucial role in the maintenance of epidermal hyperplasia in the psoriatic lesion is indicated by the beneficial clinical effect of such immunosuppressive agents as cyclosporin A, FK 506, anti-CD3, and anti-CD4 in the treatment of psoriasis (17)(18)(19)(20)(21)(22). Psoriatic keratinocytes do appear to have been modulated by T cell lymphokines in vivo, because they abnormally express class II MHC and IP-IO molecules uniquely induced on keratinocytes by the T cell product y-IFN (23-27). Indeed, T cells producing y-IFN have been cloned from psoriatic lesions (28) and they appear to be able to induce keratinocyte class II MHC and intracellular adhesion molecule expression (29) + 50 U/ml rIL-2 (Collaborative Biomedical Products) media in 24-well plates and then stimulated with PHA (lIg/ml) and allogeneic MNCs (0.5 x 106/well). After 48 h the MNCs were removed from the cultures by Ficoll-Hypaque density gradient centrifugation. 10-12 d were required for the T cells to reach resting state after PHA plus MNC activation, at which time they were then plated on fibronectin and anti-CD3-coated culture dishes in serum-free and IL-2-free AIM V media. Before cell plating the culture plates were coated initially with anti-CD3 (1 Mzg/ml) overnight 40C, washed with PBS (Gibco Laboratories) and then coated with fibronectin (Sigma Chemical Co.) (20 Yg/ ml) overnight 40C and washed with PBS, as previously described (36).Supernatants were collected 48 h after plating, sterile filtered, and stored at -70TC. Lymphokine production by activated lesional psoriatic T cells was determined by using ELISA kits for GM-CSF, IL-3, IL-4 (R&D Systems, Inc., Minneapolis, MN), y-interferon (Genzyme Corp., Boston, MA) and TNF-a (PharMingen, San Diego, CA).Clonal growth assay. Epidermal cell suspensions were prepared from normal and uninvolved psoriatic keratomes as described above. Cells were plated into 6-well culture plates (1 x 106 cells/ml, 2 ml/ well) in KBM (Gibco Laboratories) media supplemented with I1%FBS.Activated T cell supernatants and AIM V media, as control, were diluted at 1:10 with KBM and added at the time of culture initiation to the cultures (200 pl/well). The media was changed on every third day, each time supplemented with activated T cell supernatant or AIM V media as described. After 2 wk plates were fixed with 1% formalin and stained with Rhodamine B (Sigma Chemical Co.) (37).Short-term epidermal proliferation assay. Freshly isolated psoriatic uninvolved and normal epidermal cells were plated in 6-well culture plates at 1 x 106 cells/ml, 2 ml/well, and cultured for 72 h in the presence of act...

Context The high prevalence of acne vulgaris and its significant morbidity underscore the need for convenient, low-risk, and efficacious therapy. Treatment with various lasers has been reported to improve acne. Objective To evaluate the clinical efficacy of pulsed dye laser therapy in the treatment of acne. Design, Setting, and Patients Randomized, single-blind, controlled, split-face clinical trial of a volunteer sample of 40 patients aged 13 years or older with facial acne conducted at an academic referral center from August 2002 to September 2003. Intervention One or 2 nonpurpuric pulsed dye laser treatments to half of the face (fluence of 3 J/cm 2), serial blinded clinical assessments (lesion counts), and grading of acne severity using standardized bilateral serial photographs. Main Outcome Measures Comparison of the changes in lesion counts from baseline to 12 weeks between treated and untreated sides of the face and changes in photographic evidence of acne severity as graded by a panel of dermatologists blinded to treatment assignment. Results After 12 weeks, using intent-to-treat analysis with last observation carried forward, there were no significant differences between laser-treated and untreated skin for changes in mean papule counts (−4.2 vs −2.2; P=.08), mean pustule counts (0 vs −1.0; P=.12), or mean comedone counts (2.9 vs 1.6; P=.63). Grading of serial photographs confirmed the clinical assessments, showing no significant mean (SE) differences in Leeds scores (range, 1-12) for treated skin (3.98 [0.32] at baseline and 3.94 [0.27] at week 12) compared with untreated skin (3.83 [0.32] at baseline and 3.79 [0.28] at week 12) (PϾ.99). Conclusions In this study, the nonpurpuric pulsed dye laser therapy did not result in significant improvement of facial acne. More research is needed before this laser therapy may be recommended as an acne treatment.

Interferon-gamma (IFN-gamma) produced by lesional T cell clones is critical for the induction into G1 of the cell cycle by psoriatic keratinocyte stem cells; however, direct data demonstrating psoriatic lesional T cell subset IFN-gamma expression, and quantitation at a single cell level to calculate in vivo proportions, are lacking. In this study, using flow cytometry of freshly isolated normal and psoriatic lesional T cells from keratome biopsies, we found elevated CD3+, CD4+, and CD8+ T cells in all compartments of psoriatic skin, compared with normals. Using Brefeldin A to induce short-term intracellular accumulation of IFN-gamma in T cells capable of IFN-gamma production, we found that 90% of psoriatic patients have IFN-gamma-producing T cells at a greater proportion of their CD3+ cells than normals, with a mean of 16%+/-3%, as compared with 4%+/-2% in normal epidermis (p = 0.01). Expressed as density in the tissue, the IFN-gamma+ CD3+ cell number in psoriatic epidermis was 97+/-22 per mm2 surface area, as compared with 4.4+/-1.8 per mm2 of normal epidermis (p = 0.002). Thus, the total number of IFN-gamma+CD3+ T cells in the skin of a patient with 20% involvement is estimated to be 3.9 x 10(8). CD4+ and CD8+ IFN-gamma+ T cells were both elevated in psoriatic epidermis (p = 0.04 and p = 0.008, respectively) relative to normal skin. In the dermis, only 44% of patients demonstrated a higher percentage of IFN-gamma-producing T cells than did normals (p = 0.1), possibly indicating dilution, in some patients, by fresh infiltrating T cells. Interleukin-4 was not found by a combination of flow cytometry, reverse transcriptase-polymerase chain reaction, western blot, and immunoprecipitation. In conclusion, a significant portion of lesional T cells in psoriasis are IFN-gamma producing, without interleukin-4. The increased numbers of both IFN-gamma+CD4+ and IFN-gamma+CD8+ T cells indicate that both CD4+ and CD8+ IFN-gamma+ T cells are present in appropriate anatomic locations to sustain the lesional pathology.

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To quantitatively examine the epidermal and dermal cellular and molecular changes that occur after photodynamic therapy of photodamaged human skin.Design: Serial in vivo biochemical and immunohistochemical analyses after photodynamic therapy using topical 5-aminolevulinic acid (5-ALA) and pulsed-dye laser treatment.