Continuous high‐dose antigen exposure preferentially induces IL‐10, but intermittent antigen exposure induces IL‐4

IL‐10 plays a critical role in the induction of specific T‐cell tolerance. To date, whether IL‐10 induction by antigen application is dose‐ or time‐dependent remains unclear. In this study, IL‐10 induction by allergen exposure was investigated in the several schedules. Oxazolone was repeatedly applied to mouse ear, and mRNA of inflammatory cytokines in lesional skins was measured. The results indicated that continuous high‐dose antigen exposure induces IL‐4 as well as abundant IL‐10 production. Monocytes/dendritic cells and T cells are major source of IL‐10. Allergen‐specific immunotherapy is resumed before antigen scattering: preseason. We evaluated safe‐loading dose of allergens in preseasonal therapy focusing Tr1 induction. Restarting immunotherapy with high dose effectively augmented IL‐10 expression accompanied with further induction of IL‐4 and inflammatory cytokines. Therefore, the protocol restarting with low‐dose antigen is preferential to obviate the risk of exacerbation or anaphylaxis.     

Interleukin (IL)‐22, IL‐17, IL‐23, IL‐8, vascular endothelial growth factor and tumour necrosis factor‐α levels in patients with psoriasis before,during and after psoralen–ultraviolet A and narrowband ultraviolet B therapy

Background Several cross‐sectional studies have shown that different cytokines and growth factors are enhanced in psoriasis. Objectives We aimed to understand the role/relation of interleukin (IL)‐22, IL‐17, IL‐23, IL‐8, vascular endothelial growth factor (VEGF) and tumour necrosis factor (TNF)‐α in psoriasis vulgaris, addressing their levels and changes before, during and after psoralen–ultraviolet A (PUVA) and narrowband ultraviolet B (NB‐UVB) treatment. Methods A cross‐sectional and a longitudinal study (n = 34) – before (T0) and at 3 (T3), 6 (T6) and 12 (T12) weeks of NB‐UVB and PUVA therapy – were performed; 17 patients started NB‐UVB and 17 PUVA, and IL‐22, IL‐17, IL‐23, IL‐8, TNF‐α and VEGF levels were evaluated. Results At T0, compared with controls (n = 20), all the parameters were significantly higher in patients, except for TNF‐α. Both NB‐UVB and PUVA treatment gave, at T3, a significant decrease in TNF‐α and IL‐23; IL‐22 and IL‐17 decreased significantly at T6; all parameters and Psoriasis Area and Severity Index decreased significantly at T12. However, in both groups, at T12, VEGF was still significantly higher than control. Conclusions Psoriasis seems to be a complex disease in which the cytokine network is disturbed, namely in levels of IL‐22, IL‐17, IL‐23, IL‐8, TNF‐α and VEGF. NB‐UVB and PUVA follow‐up studies suggested that the reduction in the IL‐23/Th17 axis might be important in the pathogenic mechanisms of psoriasis. Further follow‐up studies of patients with psoriasis treated with these and other therapies could be very helpful for the understanding of the disturbance in the cytokine network in psoriasis and indirectly in its pathogenesis.     

Primary human keratinocytes efficiently induce IL‐1‐dependent IL‐17 in CCR6+ T cells

Abstract: Keratinocytes and activated T cells interact in skin inflammation by virtue of chemokines and cytokines. T cell‐derived IL‐17 has been described to play an important role in the course of psoriatic inflammation. In this study, we addressed how keratinocytes influence the secretion of IL‐17 in autologous T cell subsets. We found that a co‐culture of autologous keratinocytes and T cell‐receptor‐stimulated T cells markedly enhanced the production of IL‐17. Besides the importance of direct cell contact, this effect was mainly mediated by IL‐1 and could be blocked by the IL‐1 antagonist anakinra. An additional increase in IL‐17 production by IL‐23 was only seen in the presence of IL‐1, which thus plays a permissive role for the action of IL‐23. Importantly, co‐culture of keratinocytes with CCR6+ CD4+ T cells that are enriched for Th17 cells resulted in significantly higher IL‐17 production compared to co‐culture with CD4+ T cells.     

Repeated administration of IL‐31 upregulates IL‐31 receptor A (IL‐31RA) in dorsal root ganglia and causes severe itch‐associated scratching behaviour in mice

We investigated the effects of repeated administration of interleukin‐31 (IL‐31) on itch‐associated scratching counts (long‐lasting scratching, LLS) and IL‐31‐related receptor mRNA expression in mice. Intra‐dermal (i.d.) injection of IL‐31 (100 and 300 ng/site) every 12 h for 3 days significantly increased LLS. Repeated administration of IL‐31 also increased the expression of IL‐31 receptor A (IL‐31RA) and oncostatin M receptor beta (OSMRβ) in dorsal root ganglia (DRG). After the repeated administration of IL‐31 was discontinued, IL‐31RA expression decreased and reached the baseline level 2 days after the last dose of IL‐31. LLS changed along with DRG IL‐31RA expression. Moreover, IL‐31‐induced IL‐31RA protein expression was confirmed by Western blotting analysis. These data suggest that IL‐31 upregulates IL‐31RA expression in DRG neuron cell bodies, and cutaneous‐injected IL‐31‐induced itching is enhanced by DRG IL‐31RA expression in mice.     

Research in practice: IL‐22 and IL‐20: significance for epithelial homeostasis and psoriasis pathogenesis

Psoriasis vulgaris is a frequent, chronically relapsing, immune‐mediated, systemic disease with characteristic skin changes. Despite the importance of this disease there are currently limited therapeutic options indicating a need for effective, long‐lasting treatment strategies with few side effects. The most recent discoveries regarding psoriasis pathogenesis, particularly our results regarding two cytokines – IL‐22 and IL‐20 – could prove to be the foundation for such therapies. Whereas IL‐22 is mainly produced by activated T‐cell sub‐populations (Th22, Th1, Th17), monocytes, dendritic cells and keratinocytes produce IL‐20. Blood and lesional skin samples from psoriasis patients demonstrate high levels of IL‐22 and IL‐20. Interestingly, both cytokines act principally on keratinocytes and do not impact the immune system. Similar to the changes in the psoriasis epidermis these cytokines inhibit the terminal differentiation of keratinocytes although they simultaneously increase their innate defense, mobility, and the production of some chemokines. Some IL‐22 effects are amplified by TNF‐α, IL‐17, and IFN‐α. IL‐22/IL‐20 lends the reconstructed epidermis a psoriasis‐like appearance with acanthosis, hypogranularity, and hyperkeratosis. In addition, mice that constitutively express high levels of IL‐22 or IL‐20 demonstrate a psoriasis‐like appearance. A therapy counteracting IL‐22 and IL‐20 would be an innovative treatment with the potential for few side effects that would act on the final phase of psoriasis pathogenesis.     

The influence of systemic therapy on the serum levels of IL‐6 and IL‐8 in pemphigus vulgaris

Background The place of cell‐mediated immunity and cytokines in the immunopathogenesis of pemphigus vulgaris (PV) has not been fully established. Objective To assess the serum levels of pro‐inflammatory cytokines, Interleukine‐6 (IL‐6) and Interleukine‐8 (IL‐8), in PV patients before and after therapy, to evaluate the influence of therapy on the serum cytokine levels. Methods Sixty‐six newly diagnosed PV patients enrolled into the study. The serum levels of IL‐8 and IL‐6 were measured in 66 and 64 patients, respectively. According to the extent of skin and mucosal involvement, the patients were divided into two groups namely mild and severe. The serum levels of cytokines were measured using enzyme‐linked immunosorbent assay (ELISA) method before and after 4 weeks of prednisolone plus azathioprine therapy. Results In 64 patients studied for the serum level of IL‐6, the median IL‐6 level was significantly decreased from 1.6 to 0.9 pg/mL by therapy (P‐value = 0.001). Segregating the patients according to the severity of the disease, the serum level of IL‐6 did not differ significantly by therapy in patients with a mild disease. However, in patients with a severe disease the median serum level of IL‐6 decreased significantly from 1.8 to 0.9 pg/mL after therapy (P‐value = 0.001). No significant changes were found in the IL‐8 level by treatment. Conclusion The significant decrease in the IL‐6 level after therapy suggests that blocking of IL‐6 could have therapeutic benefits for the treatment of PV, particularly in severe forms.     

Cytokines of the IL‐17 family in psoriasis

Various immune cells and their messenger substances influence the development of psoriasis. Cytokines of the IL‐17 family are of particular importance. In addition to IL‐17A, which plays a central role in the pathogenesis of psoriasis, other subtypes of the IL‐17 family also have a proinflammatory effect. This review provides an up‐to‐date overview of the immunopathogenesis of psoriasis with regard to the six IL‐17 subtypes, in particular their physiological and pathogenic properties, as well as their significance for psoriasis therapy.