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- Kis, K, et al.
(författare)
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Budesonide, but not tacrolimus, affects the immune functions of normal human keratinocytes.
- 2006
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Ingår i: International Immunopharmacology. - : Elsevier BV. - 1567-5769 .- 1878-1705. ; 6:3, s. 358-68
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Tidskriftsartikel (refereegranskat)abstract
- Topical immunosuppressant therapy is widely used in the treatment of inflammatory skin diseases such as psoriasis and atopic dermatitis. Besides its beneficial therapeutic effects, application of topical anti-inflammatory drugs may render the epidermis more vulnerable to invading pathogens by suppressing innate immune responses in keratinocytes, such as cytokine production and Toll-like receptor (TLR) expression. In order to evaluate and compare the immunosuppressive effects of different immunosuppressant drugs on keratinocytes, we treated lipopolysaccharide (LPS)-stimulated and -unstimulated normal human keratinocytes with the synthetic corticosteroid budesonide and the macrolide tacrolimus. The expressions of the pattern recognition receptors (PRRs) TLR2 and TLR4 were measured by quantitative RT-PCR, pro-inflammatory cytokines IL-1alpha, IL-8 and TNF-alpha were monitored by quantitative RT-PCR and by ELISA, and alterations in TLR2 protein level were measured by flow cytometry. Budesonide had a suppressive effect on both constitutive and LPS-induced IL-8 gene expression. The amount of TNF-alpha mRNA was diminished in unstimulated keratinocytes, while TLR2 mRNA expression was markedly enhanced both in unstimulated and LPS-treated cells after incubation with budesonide. This increase in TLR2 mRNA expression was also detectable at the protein level in LPS-stimulated cells. Tacrolimus had no effect on any of the examined genes. Budesonide, but not tacrolimus, significantly inhibited the NF-kappaB-dependent luciferase reporter activity in HaCaT cells after induction with LPS or TNF-alpha. Although tacrolimus and budesonide are both effective treatments in some inflammatory skin diseases, the data provided here imply differences in local therapeutic and adverse effects of these two topical immunosuppressants.
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- Pivarcsi, Andor, et al.
(författare)
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Tumor immune escape by the loss of homeostatic chemokine expression.
- 2007
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:48, s. 19055-60
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Tidskriftsartikel (refereegranskat)abstract
- The novel keratinocyte-specific chemokine CCL27 plays a critical role in the organization of skin-associated immune responses by regulating T cell homing under homeostatic and inflammatory conditions. Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPK-signaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas. In vivo, precancerous skin lesions as well as cutaneous carcinomas showed significantly elevated levels of phosphorylated ERK compared with normal skin, suggesting the activation of EGFR-Ras signaling pathways in keratinocyte-derived malignancies. In vitro, exogenous stimulation of the EGFR-Ras signaling pathway through EGF or transfection of the dominant-active form of the Ras oncogene (H-RasV12) suppressed whereas an EGFR tyrosine kinase inhibitor increased CCL27 mRNA and protein production in keratinocytes. In mice, neutralization of CCL27 led to decreased leukocyte recruitment to cutaneous tumor sites and significantly enhanced primary tumor growth. Collectively, our data identify a mechanism of skin tumors to evade host antitumor immune responses.
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- Sonkoly, E, et al.
(författare)
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Advances in microRNAs : implications for immunity and inflammatory diseases.
- 2009
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Ingår i: Journal of Cellular and Molecular Medicine (Print). - : Wiley. - 1582-1838 .- 1582-4934. ; 13:1, s. 24-38
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Tidskriftsartikel (refereegranskat)abstract
- Since their discovery in 1993 and the introduction of the term microRNA in 2001, it has become evident that microRNAs (miRNAs) involved in many biological processes, including development, differentiation, proliferation and apoptosis. The function of miRNA the control of protein production in cells by sequence-specific targeting of mRNAs for translational repression or mRNA degradati Interestingly, immune genes are apparently preferentially targeted by miRNAs compared to the average of the human genome, indicat the significance of miRNA-mediated regulation for normal immune responses. Here, we review what is known about the role of miRN in the pathogenesis of immune-related diseases such as chronic inflammatory skin diseases, autoimmunity and viral infections.
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- Sonkoly, E, et al.
(författare)
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MicroRNAs : novel regulators in skin inflammation.
- 2008
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Ingår i: Clincal and Experimental Dermatology. - : Oxford University Press (OUP). - 0307-6938 .- 1365-2230. ; 33:3, s. 312-5
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Tidskriftsartikel (refereegranskat)abstract
- Compelling evidence indicates that microRNAs (miRNAs), short, non-protein coding RNAs, are critical for the development and survival of multicellular organisms. Recently, miRNAs were implicated in the pathogenesis of psoriasis and atopic eczema (AE), the two most common chronic inflammatory disorders in skin. In particular, miR-203, the first skin-specific miRNA, showing an intriguing expression profile being confined to skin epithelium, is specifically overexpressed in psoriasis. MiR-146a, another miRNA showing specific upregulation in psoriasis, is involved in the regulation of innate immune responses and the tumour necrosis factor (TNF)-alpha pathway. Interestingly, miR-125b, another miRNA involved in the TNF-alpha pathway, is also deregulated in psoriasis and AE. As skin inflammation may serve as a model for chronic inflammatory disorders, it is likely that miRNAs involved in skin inflammation will eventually emerge in other inflammatory or autoimmune disorders, and some of these may become disease markers and therapeutic targets. In this review we present an overview of what is currently known about the roles of miRNAs in chronic inflammatory skin disorders.
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