Interferon-gamma-dependent in vitro model for the putative keratin 17 autoimmune loop in psoriasis: exploration of pharmaco- and gene-therapeutic effects.
In 1999, A.S. Gudmundsdottir et al. have envisaged an epitope on keratin 17 (K17) as a putative psoriasis major autoantigen recognized by T cells. In a HaCaT keratinocyte model, we now demonstrate that IFN-gamma and to a less extent also TNF-alpha and TGF-alpha are able to induce K17 protein expression, in contrast to IL-1alpha, IL-1beta, IL-6, IL-8 and IL-18. This supports our hypothesis of an existing proinflammatory cytokine/K17 autoimmune loop as a presumptive positive feedback mechanism driving psoriasis etiopathogenesis. K17 overexpression was now found to also coincide with suppression of keratinocyte proliferation, e.g. induced by NF-kappa B inhibitors (Bay 11-7082 and Bay 11-7085), and thereby correlated hyperapoptosis to be encountered in psoriatic epidermis. Acitretin as an established antipsoriatic drug and the tyrosine kinase inhibitor imatinib decreased, whereas hydrocortisone as well as dexamethasone increased the IFN-gamma-induced K17 overexpression. The latter might be another mechanism explaining the well-known rebound phenomena after abrupt withdrawal of corticosteroids in psoriasis treatment. Finally, we defined a K17-directed and effective antisense oligodesoxynucleotide which may hold promise for future gene-therapeutic approaches in psoriasis.
Bockelmann
R
R
Department of Dermatology and Venereology, Otto von Guericke University, Leipziger Strasse 44, DE-39120 Magdeburg, Germany.
Horn
T
T
Gollnick
H
H
Bonnekoh
B
B
D017255:Acitretin / Q000493:pharmacokinetics; D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015551:Autoimmunity; D001549:Benzamides; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D007371:Interferon-gamma / Q000494:pharmacology*; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D007633:Keratins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007641:Keratolytic Agents / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011565:Psoriasis / Q000276:immunology* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000305:Adrenal Cortex Hormones; D000890:Anti-Infective Agents; C416282:BAY 11-7085; D001549:Benzamides; D016207:Cytokines; D007641:Keratolytic Agents; D009570:Nitriles; D016376:Oligonucleotides, Antisense; D010879:Piperazines; D011743:Pyrimidines; D013450:Sulfones; D007633:Keratins; D007371:Interferon-gamma; D000068877:Imatinib Mesylate; D017255:Acitretin