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Sorel Fitz-Gibbon,
Shuta Tomida,
Bor-Han Chiu,
Lin Nguyen,
Christine Du,
Minghsun Liu,
David Elashoff,
Marie C Erfe,
Anya Loncaric, Jenny Kim,
Robert L Modlin,
Jeff F Miller,
Erica Sodergren,
Noah Craft,
George M Weinstock,
Huiying Li
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ABSTRACT: The human skin microbiome plays important roles in skin health and disease. However, bacterial population structure and diversity at the strain level is poorly understood. We compared the skin microbiome at the strain level and genome level of Propionibacterium acnes, a dominant skin commensal, between 49 acne patients and 52 healthy individuals by sampling the pilosebaceous units on their noses. Metagenomic analysis demonstrated that while the relative abundances of P. acnes were similar, the strain population structures were significantly different in the two cohorts. Certain strains were highly associated with acne and other strains were enriched in healthy skin. By sequencing 66 previously unreported P. acnes strains and comparing 71 P. acnes genomes, we identified potential genetic determinants of various P. acnes strains in association with acne or health. Our analysis suggests that acquired DNA sequences and bacterial immune elements may play roles in determining virulence properties of P. acnes strains and some could be future targets for therapeutic interventions. This study demonstrates a previously unreported paradigm of commensal strain populations that could explain the pathogenesis of human diseases. It underscores the importance of strain level analysis of the human microbiome to define the role of commensals in health and disease.Journal of Investigative Dermatology accepted article preview online, 21 January 2013; doi:10.1038/jid.2013.21.
Journal of Investigative Dermatology 01/2013; · 6.31 Impact Factor
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Adam J Friedman,
Jenny Phan,
David O Schairer,
Jackson Champer,
Min Qin,
Aslan Pirouz,
Karin Blecher-Paz,
Ami Oren,
Phil T Liu,
Robert L Modlin, Jenny Kim
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ABSTRACT: Advances in nanotechnology have demonstrated potential application of nanoparticles (NPs) for effective and targeted drug delivery. Here we investigated the antimicrobial and immunological properties and the feasibility of using NPs to deliver antimicrobial agents to treat a cutaneous pathogen. NPs synthesized with chitosan and alginate demonstrated a direct antimicrobial activity in vitro against Propionibacterium acnes, the bacterium linked to the pathogenesis of acne. By electron microscopy (EM) imaging, chitosan-alginate NPs were found to induce the disruption of the P. acnes cell membrane, providing a mechanism for the bactericidal effect. The chitosan-alginate NPs also exhibited anti-inflammatory properties as they inhibited P. acnes-induced inflammatory cytokine production in human monocytes and keratinocytes. Furthermore, benzoyl peroxide (BP), a commonly used antiacne drug, was effectively encapsulated in the chitosan-alginate NPs and demonstrated superior antimicrobial activity against P. acnes compared with BP alone while demonstrating less toxicity to eukaryotic cells. Together, these data suggest the potential utility of topical delivery of chitosan-alginate NP-encapsulated drug therapy for the treatment of dermatologic conditions with infectious and inflammatory components.Journal of Investigative Dermatology advance online publication, 29 November 2012; doi:10.1038/jid.2012.399.
Journal of Investigative Dermatology 11/2012; · 6.31 Impact Factor
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Laura J Marinelli,
Sorel Fitz-Gibbon,
Clarmyra Hayes,
Charles Bowman,
Megan Inkeles,
Anya Loncaric,
Daniel A Russell,
Deborah Jacobs-Sera,
Shawn Cokus,
Matteo Pellegrini, Jenny Kim,
Jeff F Miller,
Graham F Hatfull,
Robert L Modlin
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ABSTRACT: ABSTRACT Investigation of the human microbiome has revealed diverse and complex microbial communities at distinct anatomic sites. The microbiome of the human sebaceous follicle provides a tractable model in which to study its dominant bacterial inhabitant, Propionibacterium acnes, which is thought to contribute to the pathogenesis of the human disease acne. To explore the diversity of the bacteriophages that infect P. acnes, 11 P. acnes phages were isolated from the sebaceous follicles of donors with healthy skin or acne and their genomes were sequenced. Comparative genomic analysis of the P. acnes phage population, which spans a 30-year temporal period and a broad geographic range, reveals striking similarity in terms of genome length, percent GC content, nucleotide identity (>85%), and gene content. This was unexpected, given the far-ranging diversity observed in virtually all other phage populations. Although the P. acnes phages display a broad host range against clinical isolates of P. acnes, two bacterial isolates were resistant to many of these phages. Moreover, the patterns of phage resistance correlate closely with the presence of clustered regularly interspaced short palindromic repeat elements in the bacteria that target a specific subset of phages, conferring a system of prokaryotic innate immunity. The limited diversity of the P. acnes bacteriophages, which may relate to the unique evolutionary constraints imposed by the lipid-rich anaerobic environment in which their bacterial hosts reside, points to the potential utility of phage-based antimicrobial therapy for acne. IMPORTANCE Propionibacterium acnes is a dominant member of the skin microflora and has also been implicated in the pathogenesis of acne; however, little is known about the bacteriophages that coexist with and infect this bacterium. Here we present the novel genome sequences of 11 P. acnes phages, thereby substantially increasing the amount of available genomic information about this phage population. Surprisingly, we find that, unlike other well-studied bacteriophages, P. acnes phages are highly homogeneous and show a striking lack of genetic diversity, which is perhaps related to their unique and restricted habitat. They also share a broad ability to kill clinical isolates of P. acnes; phage resistance is not prevalent, but when detected, it appears to be conferred by chromosomally encoded immunity elements within the host genome. We believe that these phages display numerous features that would make them ideal candidates for the development of a phage-based therapy for acne.
mBio 01/2012; 3(5). · 5.31 Impact Factor
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John S Cho,
Jamie Zussman,
Niles P Donegan,
Romela Irene Ramos,
Nairy C Garcia,
Daniel Z Uslan,
Yoichiro Iwakura,
Scott I Simon,
Ambrose L Cheung,
Robert L Modlin, Jenny Kim,
Lloyd S Miller
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ABSTRACT: Staphylococcus aureus skin infections represent a significant public health threat because of the emergence of antibiotic-resistant strains such as methicillin-resistant S. aureus (MRSA). As greater understanding of protective immune responses and more effective antimicrobial therapies are needed, a S. aureus skin wound infection model was developed in which full-thickness scalpel cuts on the backs of mice were infected with a bioluminescent S. aureus (methicillin sensitive) or USA300 community-acquired MRSA strain and in vivo imaging was used to noninvasively monitor the bacterial burden. In addition, the infection-induced inflammatory response was quantified using in vivo fluorescence imaging of LysEGFP mice. Using this model, we found that both IL-1α and IL-1β contributed to host defense during a wound infection, whereas IL-1β was more critical during an intradermal S. aureus infection. Furthermore, treatment of a USA300 MRSA skin infection with retapamulin ointment resulted in up to 85-fold reduction in bacterial burden and a 53% decrease in infection-induced inflammation. In contrast, mupirocin ointment had minimal clinical activity against this USA300 strain, resulting in only a 2-fold reduction in bacterial burden. Taken together, this S. aureus wound infection model provides a valuable preclinical screening method to investigate cutaneous immune responses and the efficacy of topical antimicrobial therapies.
Journal of Investigative Dermatology 12/2010; 131(4):907-15. · 6.31 Impact Factor
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ABSTRACT: Hyaluronic acid and onabotulinumtoxinA combination therapy has been shown to have greater clinical effectiveness than hyaluronic acid alone for glabellar furrowing, but this is not well documented for melomental fold rhytides.
To compare the efficacy of intradermal cross-linked hyaluronic acid (HA) and onabotulinumtoxinA combination therapy with the efficacy of cross-linked HA monotherapy in patients with melomental fold rhytides.
Twenty-two patients received combination therapy to a melomental fold area while also receiving cross-linked HA and a placebo saline injection to the contralateral side. Blinded physician evaluators and patient self-evaluators clinically and photographically assessed responses during standard intervals over 12 months.
The melomental folds treated with combination therapy had significantly greater aesthetic improvement than the monotherapy-treated side at 2 weeks and 1 month upon physician photographic review. Furthermore, the median time for return to pretreatment rhytides was 6.5 weeks longer in the combination therapy side. Patient assessment also revealed improvement over baseline for the combination therapy at 1 month.
Cross-linked HA and onabotulinumtoxinA combination therapy to melomental fold rhytides may provide better overall aesthetic results and longer duration of aesthetic improvement than cross-linked HA monotherapy.
Dermatologic Surgery 11/2010; 36 Suppl 3:1852-8. · 1.80 Impact Factor
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ABSTRACT: With the rise of the cosmeceutical industry, numerous formulations have surfaced with claims of reducing the clinical manifestations of photoaging. Many of these products capitalize on the positive connection the public makes with vitamins, especially with respect to their antioxidant capabilities. An impressive amount of basic science and clinical research has been conducted in both an attempt to discover novel strategies for preventing detrimental sun damage and to validate the addition of vitamins to skin care products. As dermatologists, it will be essential to provide our patients with substantiated counseling regarding the efficacy of commercial assertions. In this review, we will systematically examine the evidence supporting the use of vitamins in oral and topical formulations and provide a brief summary of the pathogenesis of photoaging. Limitations of this study include that there may be unpublished data or additional studies that may have been overlooked in our comprehensive review of this topic.
Journal of the American Academy of Dermatology 02/2010; 63(3):507-25. · 3.99 Impact Factor
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Jenny Kim
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ABSTRACT: Acne, one of the most common skin diseases, is caused by multiple factors, including Propionibacterium acnes. Studies suggest that responses to P. acnes by host immunity play important roles in its pathogenesis. Identifying immune modulators that attenuate inflammatory responses against P. acnes and the inhibition of bacterial growth may lead to novel avenues of immunologic intervention.
Journal of Investigative Dermatology 11/2008; 128(10):2353-4. · 6.31 Impact Factor
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ABSTRACT: The Profile BBL/MLP Platform used during the study was on loan to the department by Sciton, Inc., Palo Alto, CA.
Dermatologic Surgery 10/2008; 34(11):1603-8. · 1.80 Impact Factor
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ABSTRACT: Propionibacterium acnes is a critical component in the pathogenesis of acne vulgaris, stimulating the production of various inflammatory mediators, such as cytokines and chemokines, important in the local inflammatory response found in acne. This study explored the role of P. acnes and its ability to induce matrix metalloproteinases (MMPs) in primary human monocytes and how this induction is regulated by retinoids. MMP-1- and MMP-9-expressing cells were present in perifollicular and dermal inflammatory infiltrates within acne lesions, suggesting their role in acne pathogenesis. In vitro, we found that P. acnes induced MMP-9 and MMP-1 mRNA, and the expression of MMP-9, but not of MMP-1, was found to be Toll-like receptor 2-dependent. P. acnes induced the mRNA expression of tissue inhibitors of metalloproteinase (TIMP)-1, the main regulator of MMP-9 and MMP-1. Treatment of monocytes with all-trans retinoic acid (ATRA) significantly decreased baseline MMP-9 expression. Furthermore, co-treatment of monocytes with ATRA and P. acnes inhibited MMP-9 and MMP-1 induction, while augmenting TIMP-1 expression. These data indicate that P. acnes-induced MMPs and TIMPs may be involved in acne pathogenesis and that retinoic acid modulates MMP and TIMP expression, shifting from a matrix-degradative phenotype to a matrix-preserving phenotype.
Journal of Investigative Dermatology 07/2008; 128(12):2777-82. · 6.31 Impact Factor
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ABSTRACT: Propionibacterium acnes is a major etiological factor of acne, triggering an inflammatory response in part through the activation of TLR2. In this study, we demonstrate that activation of peripheral blood monocytes with P. acnes in vitro induced their differentiation into two distinct innate immune cell subsets, CD209(+) macrophages and CD1b(+) dendritic cells. Furthermore, P. acnes induced expression of mRNA for the cytokines IL-15 and GM-CSF, which differentiate CD209(+) and CD1b(+) cells, respectively. The CD209(+) cells were more effective in uptake of P. acnes, compared with the CD1b(+) cells, and demonstrated a 2-fold greater antimicrobial activity against the phagocytosed bacteria. Although CD1b(+) cells secreted inflammatory cytokines in response to both P. acnes and a TLR2 ligand control, the CD209(+) cells responded only to P. acnes. The addition of all-trans retinoic acid, a commonly used agent for the treatment of acne, directly induced differentiation of monocytes into CD209(+) macrophages and enhanced the P. acnes-mediated differentiation of the CD209(+) subset. Therefore, the differentiation of monocytes into CD209(+) macrophages and CD1b(+) dendritic cells distinctly mediate the innate immune response to P. acnes.
The Journal of Immunology 05/2008; 180(7):4919-23. · 5.79 Impact Factor
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ABSTRACT: •
Antimicrobial peptides (AMPs) are low-molecularweight proteins with a wide spectrum of activity against microbial pathogens.
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Antimicrobial peptides are amphipathic.
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Antimicrobial peptides include defensins, cathelicidins, granulysin, S-100 proteins, and a variety of other antimicrobial
proteins.
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Antimicrobial peptides play a role in acne, wound healing, psoriasis, and atopic dermatitis.
12/2007: pages 131-145;
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ABSTRACT: In our previous research, bcl-2-positive dendritic cells were seen in increased numbers in suprabasal areas of inverted follicular keratoses (IFKs) compared to seborrheic keratoses (SKs). The purpose of this study was twofold; firstly, to support that these dendritic cells are Langerhans cells and secondly, to contrast the epidermal dendritic cells in IFKs, squamous cell carcinomas (SCCs), and SKs.
Ten IFKs and five SKs previously showing bcl-2-positive dendritic cells within the epidermis were stained with CD1a. Fifteen other IFKs were stained with CD1a alone. Ten SCCs were stained with bcl-2 and CD1a.
In the 10 IFKs stained with both bcl-2 and CD1a, the density of CD1a-positive cells correlated well with the density of bcl-2-positive dendritic cells; in the five SKs, the density of CD1a-positive cells was similar to that seen in IFKs but was higher compared to the density of bcl-2-positive dendritic cells in SKs (p < 0.05). The IFKs had a significantly higher number of CD1a-positive cells compared to SCCs (p < 0.01). SCCs showed bcl-2-positive cells only within the basal layer of the normal epidermis flanking the carcinomas.
These results suggest that there is different bcl-2 regulation of CD1a-positive cells in IFKs, SKs, and SCCs.
Journal of Cutaneous Pathology 07/2006; 33(7):498-501. · 1.56 Impact Factor
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Jamie E McInturff,
Shyh-Jeun Wang,
Thomas Machleidt,
T Richard Lin,
Ami Oren,
Cheryl J Hertz,
Stephan R Krutzik,
Scott Hart,
Karin Zeh,
Daniel H Anderson,
Richard L Gallo,
Robert L Modlin, Jenny Kim
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ABSTRACT: Propionibacterium acnes is a key therapeutic target in acne, yet this bacterium has become resistant to standard antibiotic agents. We investigated whether the human antimicrobial protein granulysin is a potential candidate for the treatment of acne. Granulysin and synthetic granulysin-derived peptides possessing a helix-loop-helix motif killed P. acnes in vitro. Modification of a helix-loop-helix peptide, 31-50, by substitution of a tryptophan for the valine at amino acid 44 (peptide 31-50v44w) to increase its interaction with bacterial surfaces also increased its antimicrobial activity. Moreover, when synthesized with D- rather than L-type amino acids, this peptide (D-31-50v44w) became less susceptible to degradation by proteases and more effective in killing P. acnes. Granulysin peptides were bactericidal, demonstrating an advantage over standard bacteriostatic antibiotics in their control of P. acnes. Moreover, peptide D-31-50v44w killed P. acnes in isolated human microcomedone preparations. Importantly, peptides 31-50, 31-50v44w, and D-31-50v44w also have potential anti-inflammatory effects, as demonstrated by suppression of P. acnes-stimulated cytokine release. Taken together, these data suggest that granulysin peptides may be useful as topical therapeutic agents, providing alternatives to current acne therapies.
Journal of Investigative Dermatology 09/2005; 125(2):256-63. · 6.31 Impact Factor
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ABSTRACT: Toll-like receptors (TLR) are crucial players in the innate immune response to microbial invaders. These receptors are expressed on immune cells, such as monocytes, macrophages, dendritic cells, and granulocytes. Importantly, TLR are not only expressed by peripheral blood cells, but their expression has been demonstrated in airway epithelium and skin, important sites of host-pathogen interaction. Host cells expressing TLR are capable of recognizing conserved pathogen-associated molecular patterns, such as lipopolysaccharide and CpG DNA, and their activation triggers signaling pathways that result in the expression of immune response genes and cytokine production. As TLR are instrumental in both launching innate immune responses and influencing adaptive immunity, regulation of TLR expression at sites of disease such as in leprosy, acne, and psoriasis may be important in the pathophysiology of these diseases. Furthermore, since TLR are vital players in infectious and inflammatory diseases, they have been identified as potential therapeutic targets. Indeed, synthetic TLR agonists such as imiquimod have already established utility in treating viral pathogens and skin cancers. In the future, it seems possible there may also be drugs capable of blocking TLR activation and thus TLR-dependent inflammatory responses, providing new treatment options for inflammatory diseases.
Journal of Investigative Dermatology 08/2005; 125(1):1-8. · 6.31 Impact Factor
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ABSTRACT: Acne vulgaris is a common cutaneous disorder of the pilosebaceous follicle, affecting more than 45 million people in the United States alone. The pathogenesis of acne is multifactorial, involving abnormal hyperkeratinization, increased sebum production, hormones, cutaneous microbes, and immunological mechanisms. Many of the immunological processes that contribute to the formation of acne lesions take place at the very site of disease, the skin. Skin is an important component of the innate immune system, providing both physical barriers and rapid cellular responses by keratinocytes, Langerhans cells, and other infiltrating inflammatory cells. In this review, we discuss the ability of the innate immune system to use Toll-like receptors (TLRs) to recognize microbial patterns and initiate immune responses in cutaneous disorders. Because TLRs are vital players in infectious and inflammatory diseases, they are potential therapeutic targets. Indeed, the ability of TLRs to combat disease already has been harnessed through the development of drugs that act as TLR agonists. A better understanding of TLRs will allow for the development of new therapeutic options for cutaneous inflammatory diseases such as acne.
Seminars in Cutaneous Medicine and Surgery 07/2005; 24(2):73-8. · 2.50 Impact Factor
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Lloyd S Miller,
Ole E Sørensen,
Philip T Liu,
H Ray Jalian,
Deborah Eshtiaghpour,
Behnaz E Behmanesh,
Woosin Chung,
Timothy D Starner, Jenny Kim,
Peter A Sieling,
Tomas Ganz,
Robert L Modlin
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ABSTRACT: The expression of TLRs on epithelial cells provides a first line of defense against invading pathogens. We investigated the regulated expression and function of TLR5 and TLR9 on human keratinocytes, because we found by immunohistochemistry that these TLRs are expressed in distinct layers of the epidermis. We found that TGF-alpha, a growth and differentiation factor that is present during wound healing and in psoriasis, increased the expression of both TLR5 and TLR9 on keratinocytes. In addition, TGF-alpha regulated the function of TLR5 and TLR9, because activation with their respective ligands enhanced the production of IL-8 and human beta-defensins. These findings provide evidence that TGF-alpha up-regulates TLR expression and function, augmenting host defense mechanisms at epithelial surfaces.
The Journal of Immunology 06/2005; 174(10):6137-43. · 5.79 Impact Factor
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ABSTRACT: A major consequence of microbial infection is the tissue injury that results from the host inflammatory response. In acne, inflammation is due in part to the ability of Propionibacterium acnes to activate TLR2. Because all-trans retinoic acid (ATRA) decreases inflammation in acne, we investigated whether it regulates TLR2 expression and function. Treatment of primary human monocytes with ATRA led to the down-regulation of TLR2 as well as its coreceptor CD14, but not TLR1 or TLR4. The ability of a TLR2/1 ligand to trigger monocyte cytokine release was inhibited by pre- and cotreatment with ATRA; however, TLR4 activation was affected by cotreatment only. ATRA also down-regulated monocyte cytokine induction by P. acnes. These data indicate that ATRA exerts an anti-inflammatory effect on monocytes via two pathways, one specifically affecting TLR2/1 and CD14 expression and one independent of TLR expression. Agents that target TLR expression and function represent a novel strategy to treat inflammation in humans.
The Journal of Immunology 04/2005; 174(5):2467-70. · 5.79 Impact Factor
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Jenny Kim
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ABSTRACT: Acne vulgaris is a common disorder that affects 40-50 million people in the USA alone. The pathogenesis of acne is multifactorial, including hormonal, microbiological and immunological mechanisms. One of the factors that contributes to the pathogenesis of acne is Propionibacterium acnes; yet, the molecular mechanism by which P. acnes induces inflammation is not known. Recent studies have demonstrated that microbial agents trigger cytokine responses via Toll-like receptors (TLRs). TLRs are pattern recognition receptors that recognize pathogen-associated molecular patterns conserved among microorganisms and elicit immune responses. We investigated whether TLR2 mediates P. acnes-induced cytokine production in acne. Using transfectant cells we found that TLR2 was sufficient for NF-kappaB activation in response to P. acnes. In addition, peritoneal macrophages from wild-type, TLR6 knockout and TLR1 knockout mice, but not TLR2 knockout mice, produced IL-6 in response to P. acnes.P. acnes induced activation of IL-12 and IL-8 production by primary human monocytes, and this cytokine production was inhibited by anti-TLR2-blocking antibody. Finally, in acne lesions, TLR2 was expressed on the cell surface of macrophages surrounding pilosebaceous follicles. These data suggest that P. acnes triggers inflammatory cytokine responses in acne by activation of TLR2. As such, TLR2 may provide a novel target for the treatment of this common skin disease.
Dermatology 02/2005; 211(3):193-8. · 2.05 Impact Factor
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ABSTRACT: Acne vulgaris is a common cutaneous disorder of the pilosebaceous follicle. More than 45 million people are affected with acne vulgaris. In addition, 80% of people in the United States report that they suffered from acne at one point in life. It is estimated that US consumers spend $1.2 billion each year for the treatment of acne. Typically, lesions are pleomorphic and range from open and closed comedones to inflammatory papules, pustules, cysts, and nodules, and scarring may result. The disease is important, with a significant effect on patients' self-esteem. The pathogenesis is only partially understood and is multifactorial. Successful management of acne requires an understanding of the pathophysiology of disease. The first half of this review discusses new discoveries in the pathogenesis of acne, and the second half introduces new and time-honored therapies.
Current Opinion in Pediatrics 09/2003; 15(4):405-10. · 2.83 Impact Factor
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ABSTRACT: In response to interleukin 12 (IL-12) stimulation, a latent cytoplasmic transcription factor, Stat4 (signal transducer and activator of transcription 4), becomes tyrosine-phosphorylated and translocates into the nucleus where it binds to DNA to activate transcription. Cofactors that can directly bind and regulate Stat4 activity have not been described. We report here that PIASx, a member of the protein inhibitor of activated STAT (PIAS) family, is a negative regulator of Stat4. PIASx becomes associated with Stat4 following IL-12 stimulation in vivo. PIASx inhibits IL-12-stimulated and Stat4-dependent gene activation in human T cells. PIASx does not inhibit the DNA binding activity of Stat4. Instead PIASx is present in the Stat4-DNA binding complex. Finally the inhibitory activity of PIASx on Stat4-mediated gene activation is abolished by the histone deacetylase inhibitor trichostatin A. Our results suggest that PIASx may function as a co-repressor of Stat4.
Journal of Biological Chemistry 07/2003; 278(24):21327-30. · 4.77 Impact Factor
