Jürgen Schauber

Publications of Jürgen Schauber

• Cathelicidin LL-37: an antimicrobial peptide with a role in inflammatory skin disease.

  Authors: Markus Reinholz, Thomas Ruzicka, Jürgen Schauber

  Annals of dermatology. 05/2012; 24(2):126-35.

  Chronic inflammatory skin diseases such as atopic dermatitis, psoriasis or rosacea are very common. Although their exact pathogenesis is not completely understood all three diseases are characterizedChronic inflammatory skin diseases such as atopic dermatitis, psoriasis or rosacea are very common. Although their exact pathogenesis is not completely understood all three diseases are characterized by dysregulation of cutaneous innate immunity. Cathelicidin LL-37 is an important effector molecule of innate immunity in the skin and atopic dermatitis, psoriasis or rosacea show defects in cathelicidin expression, function or processing. In atopic dermatitis, cathelicidin induction might be disturbed resulting in defective antimicrobial barrier function. In contrast, psoriasis is characterized by overexpression of cathelicidin. However to date it is unclear whether pro- or anti-inflammatory functions of cathelicidin predominate in lesional skin in psoriasis. In rosacea, cathelicidin processing is disturbed resulting in peptide fragments causing inflammation, erythema and telangiectasias. In this review, the current evidence on the role of cathelicidin LL-37 in the pathogenesis of inflammatory skin diseases will be outlined. As cathelicidin LL-37 might also serve as a future treatment target potential novel treatment strategies for those diseases will be discussed.

• Cathelicidin LL-37: a defense molecule with a potential role in psoriasis pathogenesis.

  Authors: Yvonne Dombrowski, Jürgen Schauber

  Experimental dermatology. 05/2012; 21(5):327-30.

  Epidermal keratinocytes produce and secrete antimicrobial peptides (AMPs) that subsequently form a chemical shield on the skin surface. Cathelicidins are one family of AMPs in skin with variousEpidermal keratinocytes produce and secrete antimicrobial peptides (AMPs) that subsequently form a chemical shield on the skin surface. Cathelicidins are one family of AMPs in skin with various further immune functions. Consequently, dysfunction of these peptides has been implicated in the pathogenesis of inflammatory skin disease. In particular, the cathelicidin LL-37 is overexpressed in inflamed skin in psoriasis, binds to extracellular self-DNA released from dying cells and converts self-DNA in a potent stimulus for plasmacytoid dendritic cells (pDCs). Subsequently, pDCs secrete type I interferons and trigger an auto-inflammatory cascade. Paradoxically, therapies targeting the vitamin D pathway such as vitamin D analogues or UVB phototherapy ameliorate cutaneous inflammation in psoriasis but strongly induce cathelicidin expression in skin at the same time. Current evidence now suggests that self-DNA present in the cytosol of keratinocytes is also pro-inflammatory active and triggers IL-1β secretion in psoriatic lesions through the AIM2 inflammasome. This time, however, binding of LL-37 to self-DNA neutralizes DNA-mediated inflammation. Hence, cathelicidin LL-37 shows contrasting roles in skin inflammation in psoriasis and might serve as a target for novel therapies for this chronic skin disease.

• Vitamin D Analog Calcipotriol Suppresses the Th17 Cytokine-Induced Proinflammatory S100 "Alarmins" Psoriasin (S100A7) and Koebnerisin (S100A15) in Psoriasis.

  Authors: Zuzana Hegyi, Stephanie Zwicker, Daniela Bureik, Mark Peric, Sarah Koglin, Aleksandra Batycka-Baran, Jörg C Prinz, Thomas Ruzicka, Jürgen Schauber, Ronald Wolf

  The Journal of investigative dermatology. 03/2012;

  The antimicrobial peptides (AMP) psoriasin (S100A7) and koebnerisin (S100A15) are differently induced in psoriatic skin. They act synergistically as chemoattractants and "alarmins" to amplifyThe antimicrobial peptides (AMP) psoriasin (S100A7) and koebnerisin (S100A15) are differently induced in psoriatic skin. They act synergistically as chemoattractants and "alarmins" to amplify inflammation in psoriasis. Th17 cytokines are key players in psoriasis pathogenesis and vitamin D analogs feature anti-psoriatic effects; both of these activities could be mediated through epidermal AMP regulation. We show that supernatants of cultured psoriatic T cells induce and release psoriasin and koebnerisin from keratinocytes and the Th17 cytokines IL-17A, tumor necrosis factor-α, and IL-22 differently regulate psoriasin and koebnerisin reflecting their distinct expression pattern in normal and psoriatic skin. IL-17A is the principal inducer of both S100 and their expression is further amplified by cooperating Th17 cytokines in the micromilieu of psoriatic skin. Increased extracellular psoriasin and koebnerisin also synergize as "alarmins" to prime epidermal keratinocytes for production of immunotropic cytokines that further amplify the inflammatory response. Treatment of psoriatic plaques with the vitamin D analog calcipotriol interferes with the S100-mediated positive feedback loop by suppressing the increased production of psoriasin and koebnerisin in psoriatic skin and their Th17-mediated regulation in epidermal keratinocytes. Thus, targeting the S100-amplification loop could be a beneficial anti-inflammatory approach in psoriasis and other inflammatory skin diseases.Journal of Investigative Dermatology advance online publication, 8 March 2012; doi:10.1038/jid.2011.486.

• Narrow-band ultraviolet B exposure increases serum vitamin D levels in haemodialysis patients.

  Authors: Meri J Ala-Houhala, Katja Vähävihu, Taina Hasan, Hannu Kautiainen, Erna Snellman, Piia Karisola, Yvonne Dombrowski, Jürgen Schauber, Heikki Saha, Timo Reunala

  Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 12/2011;

  BACKGROUND: Chronic kidney disease (CKD) patients are especially prone to vitamin D insufficiency. Narrow-band ultraviolet B (NB-UVB) treatment increases serum 25-hydroxyvitamin D [25(OH)D] inBACKGROUND: Chronic kidney disease (CKD) patients are especially prone to vitamin D insufficiency. Narrow-band ultraviolet B (NB-UVB) treatment increases serum 25-hydroxyvitamin D [25(OH)D] in dermatological patients, and we studied whether it also improves vitamin D balance in CKD patients on haemodialysis.METHODS: Fifteen dialysis patients (mean age 48.3 years) and 12 healthy subjects (mean age 43.6 years) received nine NB-UVB exposures on the upper body. Serum 25(OH)D and 1,25(OH)(2)D were measured before and after the exposures. From skin biopsy specimen messenger RNA (mRNA) expression levels of CYP24A1 and CYP27B1, two enzymes needed for hydroxylation of vitamin D into its active metabolites, and of antimicrobial peptide cathelicidin, were examined.RESULTS: Before NB-UVB, mean serum 25(OH)D was 32.5 ± 10.2 nmol/L in the dialysis patients and 60.2 ± 18.0 nmol/L in the healthy subjects (P < 0.001). After eight NB-UVB exposures, serum 25(OH)D increased by 13.8 nmol/L (43%; P < 0.001) and serum 1,25(OH)(2)D by 3.3 pmol/L (27%; P = 0.002) in the dialysis patients. After NB-UVB exposures, CYP27B1 mRNA was increased (P = 0.04), whereas cathelicidin mRNA was decreased (P < 0.0001) compared to non-treated healthy subjects. One and 2 months after NB-UVB exposure, serum 25(OH)D was still 10% higher than initially in the dialysis patients.CONCLUSIONS: The present study shows that a short course of NB-UVB exposure increases significantly serum 25(OH)D and 1,25(OH)(2)D in dialysis patients. The effect is, however, short lasting suggesting that the patients need cyclic NB-UVB exposure to maintain their improved vitamin D concentration.

• Pathogenic DNA: cytosolic DNA promotes inflammation in psoriasis.

  Authors: Jürgen Schauber, Yvonne Dombrowski, Robert Besch

  Cell cycle (Georgetown, Tex.). 09/2011; 10(18):3038-9.

  Comment on: Dombrowski Y, et al. Sci Transl Med 2011; 3:82ra38.

• Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions.

  Authors: Yvonne Dombrowski, Mark Peric, Sarah Koglin, Claudia Kammerbauer, Christine Göss, David Anz, Maren Simanski, Regine Gläser, Jürgen Harder, Veit Hornung, Richard L Gallo, Thomas Ruzicka, Robert Besch, Jürgen Schauber

  Science translational medicine. 05/2011; 3(82):82ra38.

  The proinflammatory cytokine interleukin-1β (IL-1β) plays a central role in the pathogenesis and the course of inflammatory skin diseases, including psoriasis. Posttranscriptional activation of IL-1βThe proinflammatory cytokine interleukin-1β (IL-1β) plays a central role in the pathogenesis and the course of inflammatory skin diseases, including psoriasis. Posttranscriptional activation of IL-1β is mediated by inflammasomes; however, the mechanisms triggering IL-1β processing remain unknown. Recently, cytosolic DNA has been identified as a danger signal that activates inflammasomes containing the DNA sensor AIM2. In this study, we detected abundant cytosolic DNA and increased AIM2 expression in keratinocytes in psoriatic lesions but not in healthy skin. In cultured keratinocytes, interferon-γ induced AIM2, and cytosolic DNA triggered the release of IL-1β via the AIM2 inflammasome. Moreover, the antimicrobial cathelicidin peptide LL-37, which can interact with DNA in psoriatic skin, neutralized cytosolic DNA in keratinocytes and blocked AIM2 inflammasome activation. Together, these data suggest that cytosolic DNA is an important disease-associated molecular pattern that can trigger AIM2 inflammasome and IL-1β activation in psoriasis. Furthermore, cathelicidin LL-37 interfered with DNA-sensing inflammasomes, which thereby suggests an anti-inflammatory function for this peptide. Thus, our data reveal a link between the AIM2 inflammasome, cathelicidin LL-37, and autoinflammation in psoriasis, providing new potential targets for the treatment of this chronic skin disease.

• Impact of vitamin D3 on cutaneous immunity and antimicrobial peptide expression.

  Authors: Attila S Antal, Yvonne Dombrowski, Sarah Koglin, Thomas Ruzicka, Jürgen Schauber

  Dermato-endocrinology. 01/2011; 3(1):18-22.

  Antimicrobial peptides (AMPs) are effectors of cutaneous innate immunity and protect primarily against microbial infections. An array of AMPs can be found in and on the skin. Those include peptidesAntimicrobial peptides (AMPs) are effectors of cutaneous innate immunity and protect primarily against microbial infections. An array of AMPs can be found in and on the skin. Those include peptides that were first discovered for their antimicrobial properties but also proteins with antimicrobial activity first characterized for their activity as chemokines, enzymes, enzyme inhibitors and neuropeptides. Cathelicidins were among the first families of AMPs discovered in skin. They are now known to exert a dual role in innate immune defense: they have direct antimicrobial activity and will also initiate a host cellular response resulting in cytokine release, inflammation and angiogenesis. Altered cathelicidin expression and function was observed in several common inflammatory skin diseases such as atopic dermatitis, rosacea and psoriasis. Until recently the molecular mechanisms underlying cathelicidin regulation were not known. Lately, vitamin D3 was identified as the major regulator of cathelicidin expression and entered the spotlight as an immune modulator with impact on both, innate and adaptive immunity. Therapies targeting vitamin D3 signalling may provide novel approaches for the treatment of infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions through AMP regulation.

• Innate immunity in atopic dermatitis.

  Authors: Andreas Wollenberg, Helen-Caroline Räwer, Jürgen Schauber

  Clinical reviews in allergy & immunology. 12/2010; 41(3):272-81.

  Atopic dermatitis (AD) is a clinically defined, highly pruritic, chronic inflammatory skin disease. In AD patients, the combination of a genetic predisposition for skin barrier dysfunction andAtopic dermatitis (AD) is a clinically defined, highly pruritic, chronic inflammatory skin disease. In AD patients, the combination of a genetic predisposition for skin barrier dysfunction and dysfunctional innate and adaptive immune responses leads to a higher frequency of bacterial and viral skin infections. The innate immune system quickly mobilizes an unspecific, standardized first-line defense against different pathogens. Defects in this system lead to barrier dysfunction which results in increased protein allergen penetration through the epidermis and predisposes to secondary skin infections. Two loss-of-function mutations in the epidermal filaggrin gene are associated with AD. Also, inducible endogenous antibiotics such as the antimicrobial peptides cathelicidin and the beta-defensins may show defective function in lesional AD skin. Eczema herpeticum is a disseminated viral infection almost exclusively diagnosed in AD patients, which is based on unmasking of the viral entry receptor nectin-1, lack of cathelicidin production by keratinocytes, and depletion of Type I IFN-producing plasmacytoid dendritic cells from AD skin. Future therapeutic approaches to AD may include enhancement of impaired innate in addition to downregulation of dysfunctional adaptive immunity.

• Vascular endothelial growth factor (VEGF) in the pathogenesis of psoriasis--a possible target for novel therapies?

  Authors: Miriam Canavese, Fiorella Altruda, Thomas Ruzicka, Jürgen Schauber

  Journal of dermatological science. 06/2010; 58(3):171-6.

  Angiogenesis is defined as the formation of new capillaries from pre-existing blood vessels. The process of angiogenesis is tightly regulated by a balance between pro- and anti-angiogenic factors.Angiogenesis is defined as the formation of new capillaries from pre-existing blood vessels. The process of angiogenesis is tightly regulated by a balance between pro- and anti-angiogenic factors. Vascular endothelial growth factor (VEGF) is a pro-angiogenic factor and several anti-VEGF therapies are used in the treatment of diseases that are characterized by abnormal formation of blood vessels such as certain cancers and age-related macular degeneration. In addition, dysregulated angiogenesis has been observed in inflammatory diseases and might underly chronic cutaneous inflammation in psoriasis. Several experimental studies and clinical reports suggest that VEGF is involved in psoriasis pathogenesis. Among those, transgenic over-expression of VEGF in keratinocytes in mice resulted in skin inflammation and a phenotype resembling human psoriasis. In different psoriasis models, anti-VEGF antibody treatment of mice, already displaying disease symptoms, resulted in an overall improvement of the cutaneous lesions. On the molecular level human keratinocytes produce VEGF after stimulation with cytokines involved in psoriasis pathogenesis. Finally, patients with psoriasis receiving anti-VEGF treatment for cancer showed complete remission of their cutaneous symptoms. Therefore, VEGF might be an underappreciated pro-inflammatory factor in the pathogenesis of psoriasis. In this review, current knowledge on the significance of VEGF in psoriasis pathogenesis is summarized. Furthermore, current reports on treatments directed against VEGF or its receptors and their potential as future therapy for psoriasis are discussed.

• UV-B-triggered induction of vitamin D3 metabolism differentially affects antimicrobial peptide expression in keratinocytes.

  Authors: Mark Peric, Bodo Lehmann, Gabriela Vashina, Yvonne Dombrowski, Sarah Koglin, Michael Meurer, Thomas Ruzicka, Jürgen Schauber

  The Journal of allergy and clinical immunology. 03/2010; 125(3):746-9.

• Control of cutaneous antimicrobial peptides by vitamin D3.

  Authors: Yvonne Dombrowski, Mark Peric, Sarah Koglin, Thomas Ruzicka, Jürgen Schauber

  Archives of dermatological research. 03/2010; 302(6):401-8.

  Constant exposure to a wide variety of microbial pathogens represents a major challenge for our skin. Antimicrobial peptides (AMPs) are mediators of cutaneous innate immunity and protect primarilyConstant exposure to a wide variety of microbial pathogens represents a major challenge for our skin. Antimicrobial peptides (AMPs) are mediators of cutaneous innate immunity and protect primarily against microbial infections. Cathelicidins were among the first AMPs identified in human skin and recent evidence suggests that they exert a dual role in innate immune defense: At first, due to their antimicrobial activity they kill pathogens directly. In addition, these peptides initiate a potent host response to infection resulting in cytokine release, inflammation and a cellular response. Disturbed cathelicidin expression and function was observed in several common inflammatory skin diseases, such as psoriasis where cathelicidin peptide converts inert self-DNA and self-RNA into an autoimmune stimulus. In atopic dermatitis decreased levels of cathelicidin facilitating microbial superinfections have been discussed. Furthermore, abnormally processed cathelicidin peptides induce inflammation and a vascular response in rosacea. Until recently, the molecular mechanisms underlying cathelicidin regulation were unknown. Recently, the vitamin D3 pathway was identified as the major regulator of cathelicidin expression. Consequently, vitamin D3 entered the spotlight as an immune modulator with impact on both innate and adaptive immunity. Therapies targeting vitamin D3 signaling may provide new approaches for infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions.

• The Host Defense Peptide Cathelicidin Is Required for NK Cell-Mediated Suppression of Tumor Growth.

  Authors: Amanda S Büchau, Shin Morizane, Janet Trowbridge, Jürgen Schauber, Paul Kotol, Jack D Bui, Richard L Gallo

  Journal of immunology (Baltimore, Md. : 1950). 11/2009;

  Tumor surveillance requires the interaction of multiple molecules and cells that participate in innate and the adaptive immunity. Cathelicidin was initially identified as an antimicrobial peptide,Tumor surveillance requires the interaction of multiple molecules and cells that participate in innate and the adaptive immunity. Cathelicidin was initially identified as an antimicrobial peptide, although it is now clear that it fulfills a variety of immune functions beyond microbial killing. Recent data have suggested contrasting roles for cathelicidin in tumor development. Because its role in tumor surveillance is not well understood, we investigated the requirement of cathelicidin in controlling transplantable tumors in mice. Cathelicidin was observed to be abundant in tumor-infiltrating NK1.1(+) cells in mice. The importance of this finding was demonstrated by the fact that cathelicidin knockout mice (Camp(-/-)) permitted faster tumor growth than wild type controls in two different xenograft tumor mouse models (B16.F10 and RMA-S). Functional in vitro analyses found that NK cells derived from Camp(-/-) versus wild type mice showed impaired cytotoxic activity toward tumor targets. These findings could not be solely attributed to an observed perforin deficiency in freshly isolated Camp(-/-) NK cells, because this deficiency could be partially restored by IL-2 treatment, whereas cytotoxic activity was still defective in IL-2-activated Camp(-/-) NK cells. Thus, we demonstrate a previously unrecognized role of cathelicidin in NK cell antitumor function.

• VDR and MEK-ERK dependent induction of the antimicrobial peptide cathelicidin in keratinocytes by lithocholic acid.

  Authors: Mark Peric, Sarah Koglin, Yvonne Dombrowski, Kathrin Groß, Eva Bradac, Thomas Ruzicka, Jürgen Schauber

  Molecular immunology. 10/2009;

  Cathelicidin is an antimicrobial peptide (AMP) and signaling molecule in innate immunity and a direct target of 1,25-dihydroxyvitamin D3 (1,25D3) in primary human keratinocytes (NHEK). The expressionCathelicidin is an antimicrobial peptide (AMP) and signaling molecule in innate immunity and a direct target of 1,25-dihydroxyvitamin D3 (1,25D3) in primary human keratinocytes (NHEK). The expression of cathelicidin is dysregulated in various skin diseases and its regulation differs depending on the epithelial cell type. The secondary bile acid lithocholic acid (LCA) is a ligand of the vitamin D receptor (VDR) and can carry out in vivo functions of vitamin D3. Therefore we analyzed cathelicidin mRNA- and peptide expression levels in NHEK and colonic epithelial cells (Caco-2) after stimulation with LCA. We found increased expression of cathelicidin mRNA and peptide in NHEK, in Caco-2 colon cells no effect was observed after LCA stimulation. The VDR as well as MEK-ERK signaled the upregulation of cathelicidin in NHEK induced by LCA. Collectively, our data indicate that cathelicidin induction upon LCA treatment differs in keratinocytes and colonic epithelial cells. Based on these observations LCA-like molecules targeting cathelicidin could be designed for the treatment of cutaneous diseases that are characterized by disturbed cathelicidin expression.

• Antimicrobial peptides and the skin immune defense system.

  Authors: Jürgen Schauber, Richard L Gallo

  The Journal of allergy and clinical immunology. 10/2009; 124(3 Suppl 2):R13-8.

  Our skin is constantly challenged by microbes but is rarely infected. Cutaneous production of antimicrobial peptides (AMPs) is a primary system for protection, and expression of some AMPs furtherOur skin is constantly challenged by microbes but is rarely infected. Cutaneous production of antimicrobial peptides (AMPs) is a primary system for protection, and expression of some AMPs further increases in response to microbial invasion. Cathelicidins are unique AMPs that protect the skin through 2 distinct pathways: (1) direct antimicrobial activity and (2) initiation of a host response resulting in cytokine release, inflammation, angiogenesis, and reepithelialization. Cathelicidin dysfunction emerges as a central factor in the pathogenesis of several cutaneous diseases, including atopic dermatitis, in which cathelicidin is suppressed; rosacea, in which cathelicidin peptides are abnormally processed to forms that induce inflammation; and psoriasis, in which cathelicidin peptide converts self-DNA to a potent stimulus in an autoinflammatory cascade. Recent work identified vitamin D3 as a major factor involved in the regulation of cathelicidin. Therapies targeting control of cathelicidin and other AMPs might provide new approaches in the management of infectious and inflammatory skin diseases.

• Vitamin D analogs differentially control antimicrobial peptide/"alarmin"expression in psoriasis.

  Authors: Mark Peric, Sarah Koglin, Yvonne Dombrowski, Katrin Gross, Eva Bradac, Amanda Büchau, Andreas Steinmeyer, Ulrich Zügel, Thomas Ruzicka, Jürgen Schauber

  PloS one. 02/2009; 4(7):e6340.

  Antimicrobial peptides (AMPs) are strongly expressed in lesional skin in psoriasis and play an important role as proinflammatory "alarmins" in this chronic skin disease. Vitamin D analogs likeAntimicrobial peptides (AMPs) are strongly expressed in lesional skin in psoriasis and play an important role as proinflammatory "alarmins" in this chronic skin disease. Vitamin D analogs like calcipotriol have antipsoriatic effects and might mediate this effect by changing AMP expression. In this study, keratinocytes in lesional psoriatic plaques showed decreased expression of the AMPs beta-defensin (HBD) 2 and HBD3 after topical treatment with calcipotriol. At the same time, calcipotriol normalized the proinflammatory cytokine milieu and decreased interleukin (IL)-17A, IL-17F and IL-8 transcript abundance in lesional psoriatic skin. In contrast, cathelicidin antimicrobial peptide expression was increased by calcipotriol while psoriasin expression remained unchanged. In cultured human epidermal keratinocytes the effect of different vitamin D analogs on the expression of AMPs was further analyzed. All vitamin D analogs tested blocked IL-17A induced HBD2 expression by increasing IkappaB-alpha protein and inhibition of NF-kappaB signaling. At the same time vitamin D analogs induced cathelicidin through activation of the vitamin D receptor and MEK/ERK signaling. These studies suggest that vitamin D analogs differentially alter AMP expression in lesional psoriatic skin and cultured keratinocytes. Balancing AMP "alarmin" expression might be a novel goal in treatment of chronic inflammatory skin diseases.

• IL-17A Enhances Vitamin D3-Induced Expression of Cathelicidin Antimicrobial Peptide in Human Keratinocytes.

  Authors: Mark Peric, Sarah Koglin, Song-Min Kim, Shin Morizane, Robert Besch, Jörg C Prinz, Thomas Ruzicka, Richard L Gallo, Jürgen Schauber

  Journal of immunology (Baltimore, Md. : 1950). 01/2009; 181(12):8504-12.

  Cathelicidin is strongly expressed in lesional skin in psoriasis and may play an important role as both an antimicrobial peptide and as an autoinflammatory mediator in this chronic skin disease. TheCathelicidin is strongly expressed in lesional skin in psoriasis and may play an important role as both an antimicrobial peptide and as an autoinflammatory mediator in this chronic skin disease. The mechanism of increased cathelicidin in psoriatic keratinocytes is not known, but recent observations have found that psoriasis has abundant Th17 cells that produce IL-17A and IL-22. We found that human keratinocytes stimulated with supernatants from T cells isolated from lesional psoriatic skin increased expression of cathelicidin when stimulated in the presence of 1,25-dihydroxyvitamin D(3) (1,25D(3)). This increase was signaled through the IL-17RA. In vitro, IL-17A, but not IL-22, enhanced cathelicidin mRNA and peptide expression in keratinocytes dependent on the presence of 1,25D(3). At the same time, coincubation with 1,25D(3) blocked induction of human beta-defensin 2 (HBD2), IL-6, and IL-8, which are other target genes of IL-17A. Act1, an adaptor associated with IL-17RA and essential for IL-17A signaling, mediated cathelicidin induction, as its suppression by small interfering RNA inhibited HBD2 and cathelicidin. Both, 1,25D(3) and IL-17A signaled cathelicidin induction through MEK-ERK. These results suggest that increased IL-17A in psoriatic skin increases cathelicidin through a vitamin D(3)-, Act1-, and MEK-ERK-dependent mechanism. Therapy targeting this cathelicidin-regulating system might be beneficial in patients suffering from psoriasis.

• The vitamin D pathway: a new target for control of the skin's immune response?

  Authors: Jürgen Schauber, Richard L Gallo

  Experimental dermatology. 07/2008;

  The surface of our skin is constantly challenged by a wide variety of microbial pathogens, still cutaneous infections are relatively rare. Within cutaneous innate immunity the production ofThe surface of our skin is constantly challenged by a wide variety of microbial pathogens, still cutaneous infections are relatively rare. Within cutaneous innate immunity the production of antimicrobial peptides (AMPs) is a primary system for protection against infection. Many AMPs can be found on the skin, and these include molecules that were discovered for their antimicrobial properties, and other peptides and proteins first known for activity as chemokines, enzymes, enzyme inhibitors and neuropeptides. Cathelicidins were among the first familiesf of AMPs discovered on the skin. They are now known to have two distinct functions; they have direct antimicrobial activity and will initiate a host cellular response resulting in cytokine release, inflammation and angiogenesis. Dysfunction of cathelicidin is relevant in the pathogenesis of several cutaneous diseases including atopic dermatitis where cathelicidin induction is suppressed, rosacea, where cathelicidin peptides are abnormally processed to forms that induce cutaneous inflammation and a vascular response, and psoriasis, where a cathelicidin peptide can convert self-DNA to a potent stimulus of an autoinflammatory cascade. Recent work has unexpectedly identified vitamin D3 as a major factor involved in the regulation of cathelicidin expression. Therapies targeting the vitamin D3 pathway and thereby cathelicidin may provide new treatment modalities in the management of infectious and inflammatory skin diseases.

• Pimecrolimus Enhances TLR2/6-Induced Expression of Antimicrobial Peptides in Keratinocytes.

  Authors: Amanda S Büchau, Jürgen Schauber, Thomas Hultsch, Anton Stuetz, Richard L Gallo

  The Journal of investigative dermatology. 06/2008;

  Calcineurin inhibitors are potent inhibitors of T-cell-receptor mediated activation of the adaptive immune system. The effects of this class of drug on the innate immune response system are notCalcineurin inhibitors are potent inhibitors of T-cell-receptor mediated activation of the adaptive immune system. The effects of this class of drug on the innate immune response system are not known. Keratinocytes are essential to innate immunity in skin and rely on toll-like receptors (TLRs) and antimicrobial peptides to appropriately recognize and respond to injury or microbes. In this study we examined the response of cultured human keratinocytes to pimecrolimus. We observed that pimecrolimus enhances distinct expression of cathelicidin, CD14, and human beta-defensin-2 and beta-defensin-3 in response to TLR2/6 ligands. Some of these responses were further enhanced by 1,25 vitamin D3. Pimecrolimus also increased the functional capacity of keratinocytes to inhibit growth of Staphylococcus aureus and decreased TLR2/6-induced expression of IL-10 and IL-1beta. Furthermore, pimecrolimus inhibited nuclear translocation of NFAT and NF-kappaB in keratinocytes. These observations uncover a previously unreported function for pimecrolimus in cutaneous innate host defense.Journal of Investigative Dermatology advance online publication, 22 May 2008; doi:10.1038/jid.2008.135.

• Histone acetylation in keratinocytes enables control of the expression of cathelicidin and CD14 by 1,25-dihydroxyvitamin D3.

  Authors: Jürgen Schauber, Yuko Oda, Amanda S Büchau, Qian-Chun Yun, Andreas Steinmeyer, Ulrich Zügel, Daniel D Bikle, Richard L Gallo

  The Journal of investigative dermatology. 05/2008; 128(4):816-24.

  Hormonally active vitamin D(3)-1,25-dihydroxyvitamin D(3) (1,25D3)-acts as a signaling molecule in cutaneous immunity by increasing pattern recognition through Toll-like receptor-2 (TLR2), andHormonally active vitamin D(3)-1,25-dihydroxyvitamin D(3) (1,25D3)-acts as a signaling molecule in cutaneous immunity by increasing pattern recognition through Toll-like receptor-2 (TLR2), and increasing the expression and function of antimicrobial peptides. Here we show that the actions of 1,25D3 on keratinocyte innate immune responses are influenced by histone acetylation and require the steroid receptor coactivator 3 (SRC3), which mediates inherent histone acetyltransferase (HAT) activity. SRC3 was detected in the suprabasal and granular layer of the skin, similar to cathelicidin expression. HAT activity was important to keratinocyte cathelicidin expression as the combination of histone deacetylase inhibitors (HDACi) (butyrate or trichostatin A) and 1,25D3 increased cathelicidin and CD14 expression and enhanced the antimicrobial function of keratinocytes against Staphylococcus aureus. This treatment, or activation of TLR2, also directly increased acetylation of histone 4. Small interfering RNA silencing of the vitamin D receptor or SRC3 blocked the induction of cathelicidin and CD14 by 1,25D3. HDACi could not reverse this effect or influence cathelicidin in the absence of 1,25D3, suggesting that both are necessary for function. These studies demonstrate that the epigenetic control of gene transcription by histone acetylation is important for 1,25D3-regulated antimicrobial and TLR function of keratinocytes, essential elements of the innate immune response of the skin.

• Vitamin D deficiency and asthma: not a strong link--yet.

  Authors: Jürgen Schauber, Richard L Gallo

  The Journal of allergy and clinical immunology. 04/2008; 121(3):782-3; author reply 783-4.