17-(dimethylaminoethylamino)-17-demethoxygeldanamycin and Pemphigoid--Bullous

The chaperone heat shock protein 90 (Hsp90), a cell stress-inducible molecule that regulates activity of many client proteins responsible for cellular growth, differentiation and apoptosis, has been proposed as an important therapeutic target in patients with malignancies. More recently, its active participation in (auto)immune processes has been recognized as evidenced by amelioration of inflammatory disease pathways through pharmacological inhibition of Hsp90 in rodent models of autoimmune encephalomyelitis, rheumatoid arthritis and systemic lupus erythematosus. Based on own current research results, this viewpoint essay provides important insights that Hsp90 is also involved as a notable pathophysiological factor in autoimmune blistering dermatoses including epidermolysis bullosa acquisita, bullous pemphigoid and possibly dermatitis herpetiformis. The observed in vitro, ex vivo and in vivo efficacy of anti-Hsp90 treatment in experimental models of autoimmune bullous diseases and its underlying multimodal anti-inflammatory mechanisms of interference with key contributors to autoimmune-mediated blister formation supports the introduction of selective non-toxic Hsp90 inhibitors into the clinical setting for the treatment of patients with these disorders.

Topics: Animals; Anti-Inflammatory Agents; Autoantibodies; Autoimmune Diseases; Benzoquinones; Clinical Trials as Topic; Cytokines; Dermatitis Herpetiformis; Disease Models, Animal; Drug Evaluation, Preclinical; Epidermolysis Bullosa Acquisita; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Mice; Molecular Targeted Therapy; Neutrophils; Oligopeptides; Pemphigoid, Bullous; Respiratory Burst; Skin Diseases, Vesiculobullous; T-Lymphocyte Subsets

Bullous pemphigoid (BP) is the most common subepidermal autoimmune blistering skin disease characterized by autoantibodies against the hemidesmosomal proteins BP180 and BP230. The cell stress chaperone heat shock protein 90 (Hsp90) has been implicated in inflammatory responses, and recent evidence suggests that it represents a novel treatment target in autoimmune bullous diseases. The aim of the study was to investigate the contribution of Hsp90 to the proinflammatory cytokine production in keratinocytes induced by autoantibodies to BP180 from BP patient serum. HaCaT cells were treated with purified human BP or normal IgG in the absence or presence of the Hsp90 blocker 17-DMAG and effects on viability, interleukin 6 (IL-6) and IL-8 (cytokines critical for BP pathology), NFκB (their major transcription factor), and Hsp70 (marker of effective Hsp90 inhibition and potent negative regulator of inflammatory responses) were investigated. We found that BP IgG stimulated IL-6 and IL-8 release from HaCaT cells and that non-toxic doses of 17-DMAG inhibited this IL-8, but not IL-6 secretion in a dose- and time-dependent fashion. Inhibition of this IL-8 production was also observed at the transcriptional level. In addition, 17-DMAG treatment blunted BP IgG-mediated upregulation of NFκB activity and was associated with Hsp70 induction. This study provides important insights that Hsp90 is involved as crucial regulator in anti-BP180 IgG-induced production of keratinocyte-derived IL-8. By adding to the knowledge of the multimodal anti-inflammatory effects of Hsp90 blockade, our data further support the introduction of Hsp90 inhibitors into the clinical setting for treatment of autoimmune diseases, especially for BP.

Topics: Anti-Inflammatory Agents; Autoantibodies; Autoantigens; Benzoquinones; Cell Line; Collagen Type XVII; Dose-Response Relationship, Drug; HSP90 Heat-Shock Proteins; Humans; Immunoglobulin G; Inflammation Mediators; Interleukin-6; Interleukin-8; Keratinocytes; Lactams, Macrocyclic; NF-kappa B; Non-Fibrillar Collagens; Pemphigoid, Bullous; Time Factors