Participation of interferons in psoriatic inflammation

Interferons are multifunctional cytokines not expressed in the skin under normal physiological conditions. However, they are overexpressed in serum and skin lesions of patients with psoriasis and play an important role in the pathogenesis of the disease. Interferons act directly on skin resident cells and recruit and modulate inflammatory cells, thereby exacerbating psoriatic inflammation. They upregulate the expression of relevant cytokines and chemokines, facilitate excessive proliferation of keratinocytes, and enhance the formation of poorly differentiated dermal microvessels. In this review, we summarized the pathogenic effect of interferons on psoriasis and also discussed the therapeutic strategies targeting interferons.     

The pathophysiological role of dendritic cell subsets in psoriasis

Psoriasis is a chronic inflammatory disorder characterized by an erythematous scaly plaque of the skin and is occasionally accompanied by systemic complications. In the psoriatic lesions, an increased number of cytokine-producing dendritic cells and activated T cells are observed, which indicate that psoriasis is a prototype of an immune-mediated dermatosis. During the last decade, emerging studies demonstrate novel roles for the dendritic cell subsets in the process of disease initiation and maintenance of psoriasis. In addition, recently discovered anti-psoriatic therapies, which specifically target inflammatory cytokines produced by lesional dendritic cells, bring much better clinical improvement compared to conventional treatments. These new therapies implicate the crucial importance of dendritic cells in psoriasis pathogenesis. This review will summarize and discuss the dendritic cell subsets of the human skin and their pathophysiological involvement in psoriasis based on mouse- and patient-oriented studies. [BMB Reports 2014; 47(2): 60-68]     

细胞因子在脑缺血损伤中的作用研究进展

脑缺血一旦发生,往往引起不同程度的脑损伤。缺血脑组织会产生一系列复杂的病理生理学改变。一组称为细胞因子的多肽调节物质在脑缺血损伤过程中起着关键的作用。包括神经细胞在内的多种细胞能够产生和分泌细胞因子,它们的表达时相性和作用各不相同。脑缺血引起TNF-α、IL-1、IL-6、IL-8、IL-10和FKN等多种细胞因子的表达和释放,进而触发有关损伤和修复的应答。这些参与脑缺血损伤的细胞因子能通过复杂的细胞因子网络对中枢神经系统发挥着毒性或保护效应。探究它们在脑缺血损伤中的确切作用将有助于神经系统疾病的临床治疗。现对几种关键的细胞因子综述如下。     

Contradictory functions (activation/termination) of neutrophil proteinase 3 enzyme (PR3) in interleukin-33 biological activity

IL-1 family ligand does not possess a typical hydrophobic signal peptide and needs a processing enzyme for maturation. The maturation process of IL-33 (IL-1F11), a new member of the IL-1 family ligand, remains unclear. Precursor IL-33 ligand affinity column isolates neutrophil proteinase 3 (PR3) from human urinary proteins. PR3 is a known IL-1 family ligand-processing enzyme for IL-1β (IL-1F2) and IL-18 (IL-1F4), including other inflammatory cytokines. We investigated PR3 in the maturation process of precursor IL-33 because we isolated urinary PR3 by using the precursor IL-33 ligand affinity column. PR3 converted inactive human and mouse precursor IL-33 proteins to biological active forms; however, the increase of PR3 incubation time abrogated IL-33 activities. Unlike caspase-1-cleaved precursor IL-18, PR3 cut precursor IL-33 and IL-18 at various sites and yielded multibands. The increased incubation period of PR3 abated mature IL-33 in a time-dependent manner. The result is consistent with the decreased bioactivity of IL-33 along with the increased PR3 incubation time. Six different human and mouse recombinant IL-33 proteins were expressed by the predicted consensus amino acid sequence of PR3 cleavage sites and tested for bioactivities. The human IL-33/p1 was highly active, but human IL-33/p2 and p3 proteins were inactive. Our results suggest the dual functions (activation/termination) of PR3 in IL-33 biological activity.     

Lysophosphatidylcholine aggravates contact hypersensitivity by promoting neutrophil infiltration and IL17 expression

Lysophosphatidylcholine (LPC) is a bioactive lysolipid known to contribute to the development of lung allergic diseases. However, it remains unknown whether LPC possesses proinflammatory properties in the skin as well. Here, we investigated this issue by injection of LPC into the murine contact hypersensiti-vity (CHS) model induced by 2,4-dinitrofluorobenzene (DNFB). LPC increased the expression of IL17, recruited more neutrophils, and eventually aggravated the CHS in the skins. Moreover, the effects of LPC diminished after neutralizing IL17 or depleting neutrophils. Mechanistically, LPC upregulated not only IL17 but also CXCL1 and CXCL2 in a G2A-dependent manner. Taken together, our study demonstrated that the upregulation of LPC could contribute to allergic skin inflammation by increasing IL17 expression and neutrophil recruitment via G2A receptor.     

The direct action of 1alpha,25(OH)2-vitamin D3 on purified mouse Langerhans cells

The action of vitamin D(3) on Langerhans cells (LCs) is not well understood. Using highly purified murine LCs (>95%), we investigated the direct action of 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) on their functions. 1,25(OH)(2)D(3) inhibited the expression of cell surface molecules including I-A(d), CD40, CD80, and CD86, leading to impaired ability of LCs to stimulate allogenic T cells in the mixed leukocyte reaction. Furthermore, this reagent inhibited chemotaxis of LCs to CCL21 and their survival. Interestingly, 1,25(OH)(2)D(3) reduced the IL-10 production by LCs, whereas the production of IL-6 and IL-12p40 upon activation by CD40 ligation was enhanced. With regard to inflammatory cytokines and chemokines, 1,25(OH)(2)D(3) upregulated the production of IL-1beta, CCL3, CCL4, and CCL5. The production of Th2-type chemokines, represented by CL17 and CCL22, was inhibited, whereas IFN-gamma-triggered production of Th1-type chemokines, represented by CXCL9, CXCL10, and CXCL11, was augmented. These data indicate that the mode of regulation of cytokine and chemokine production in association with 1,25(OH)(2)D(3) treatment seems to be another characteristic discriminating LCs from classical myeloid dendritic cells.     

Cytokines 2017 in Kanazawa: Looking beyond the horizon of integrated cytokine research from the sea of Japan

At the 5th Annual meeting of the International Cytokine and Interferon Society held in Kanazawa, Japan from Oct. 29–Nov. 2 2017, new research was presented in the broad field of cytokine and interferon research. The meeting provided an outstanding platform for investigators in basic science and clinical research to communicate, share and discuss their recent findings in this fast moving area of research.     

Meprin Metalloproteases Inactivate Interleukin 6

Meprins have been implicated in the pathogenesis of several inflammatory diseases, including inflammatory bowel disease, in which the cytokine IL-6 is a prominent effector molecule. Because IL-6 levels are elevated markedly in meprin α and α/β knockout mice in an experimental model of inflammatory bowel disease, the interaction between meprins and IL-6 was studied. The results demonstrate that rodent and human meprin A and B cleave IL-6 to a smaller product and, subsequently, are capable of extensive degradation of the cytokine. Analysis of the limited degradation product formed by meprin A indicated that three to five amino acids are removed from the C terminus of the cytokine. Meprin A and meprin B cleaved IL-6 with micromolar affinities (K_m of 4.7 and 12.0 μm, respectively) and with high efficiencies (k_cat/K_m of 0.2 and 2.5 (m⁻¹/s⁻¹) × 10⁶, respectively). These efficiency constants are among the highest for known meprin substrates. Madin-Darby canine kidney cells transiently transfected with meprin α or meprin β constructs also cleave exogenous IL-6. Both human and murine IL-6 cleaved by meprin A or B are inactivated, as demonstrated by their decreased capability to stimulate proliferation of B9 cells. These results are consistent with the proposition that one function of meprin metalloproteases is to modulate inflammation by inactivating IL-6.     

Cytokines in skin lesions of psoriasis

Cytokine levels were compared in aqueous extracts of stratum corneum from psoriatic lesions and normal heel. Samples from heel contained high levels of interleukin-1 alpha (IL-1 alpha) and beta measured in immunoassays, although only the IL-1 alpha was biologically active. No other cytokines could be detected in heel samples. Interleukin-1 (IL-1) levels were dramatically reduced in lesional samples. A neutrophil chemoattractant was found in all lesional extracts, and was demonstrated to be mainly interleukin-8 (IL-8) using a specific neutralizing antiserum. Tumor necrosis factor alpha (TNF-alpha) and beta (TNF-beta), and interferon alpha (IFN-alpha) and gamma (IFN-gamma) were detected in lesional extracts using immunoassays, however, no equivalent biological activities could be detected. Interleukins 2 (IL-2), 4 (IL-4), and 6 (IL-6), granulocyte and granulocyte/macrophage colony stimulating factor (GM-CSF), could not be detected in any samples. IL-8 is therefore the only biologically active cytokine shown in this study to be elevated in psoriatic lesional extracts, and may therefore play a role in the pathogenesis of the disease.     

Association between an interleukin 1 receptor,type I promoter polymorphism and self-reported attentional function in women with breast cancer

Subgroups of patients with breast cancer may be at greater risk for cytokine-induced changes in cognitive function after diagnosis and during treatment. The purposes of this study were to identify subgroups of patients with distinct trajectories of attentional function and evaluate for phenotypic and genotypic (i.e., cytokine gene polymorphisms) predictors of subgroup membership. Self-reported attentional function was evaluated in 397 patients with breast cancer using the Attentional Function Index before surgery and for six months after surgery (i.e., seven time points). Using growth mixture modeling, three attentional function latent classes were identified: High (41.6%), Moderate (25.4%), and Low-moderate (33.0%). Patients in the Low-moderate class were significantly younger than those in the High class, with more comorbidities and lower functional status than the other two classes. No differences were found among the classes in years of education, race/ethnicity, or other clinical characteristics. DNA was recovered from 302 patients’ samples. Eighty-two single nucleotide polymorphisms among 15 candidate genes were included in the genetic association analyses. After controlling for age, comorbidities, functional status, and population stratification due to race/ethnicity, IL1R1 rs949963 remained a significant genotypic predictor of class membership in the multivariable model. Carrying the rare “A” allele (i.e., GA + AA) was associated with a twofold increase in the odds of belonging to a lower attentional function class (OR: 1.98; 95% CI: 1.18, 3.30; p = .009). Findings provide evidence of subgroups of women with breast cancer who report distinct trajectories of attentional function and of a genetic association between subgroup membership and an IL1R1 promoter polymorphism.     

SEF/IL-17R (SEFIR) Is Not Enough: AN EXTENDED SEFIR DOMAIN IS REQUIRED FOR IL-17RA-MEDIATED SIGNAL TRANSDUCTION*

IL-17, the hallmark cytokine of the Th17 population, mediates immunity to extracellular pathogens and promotes autoimmune immunopathology. The signaling mechanisms triggered by the IL-17 receptor (IL-17RA) and related receptors are strikingly different from other cytokine subclasses. Namely, IL-17Rs contain a conserved SEF/IL-17R (SEFIR) subdomain that engages Act1, leading to activation of TRAF6, NF-κB, and other events. Although the SEFIR is critical for signaling, the molecular details of the functional subdomains within IL-17RA remain poorly characterized. Here, we provide a detailed structure-function analysis delineating the C-terminal boundary of the SEFIR-containing region of IL-17RA. We show that functionality of this domain requires a large extension to the previously identified SEFIR motif. In contrast to the SEFIR, this extension is not conserved among IL-17R family members. Surprisingly, Act1 recruitment is not sufficient for downstream signaling activation, whereas ubiquitination of TRAF6 correlates tightly with functional receptors. We further demonstrate that IL-17RA exhibits signaling properties that are nonredundant with other IL-17R family members. Finally, we report that IL-17 signals synergistically with lymphotoxin-α3, using the same signaling motifs within IL-17RA. These studies provide new insight into the structure-function relationships of IL-17RA and reveal distinct signaling differences among IL-17R family members.     

Th17细胞的分化、调节及其主要细胞因子和功能

近几年来以分泌白介素17(interleukin 17,IL-17)为特征的辅助性T细胞Th17(T help cell 17,Th17)细胞被认为是有区别于Th1(T help cell 1,Th1)、Th2(T help cell 2,Th2)新型的细胞亚群,它的发现改变了以往人们只将Th细胞分为Th1、Th2的传统分类认识。Th17细胞参与了自身免疫疾病、肿瘤的发生及机体各种炎症的发病机制,其分泌的细胞因子在生物学功能中发挥了极其重要的作用。同时Th17细胞的活化需要各种转化生长因子、IL-6(interleukin 6,IL-6)、IL-23(interleukin 23,IL-23)等细胞因子的参与,活化的Th17细胞同时再进一步的促进各种细胞因子的分泌,以通过分泌IL-17、IL-21(interleukin 21,IL-21)、IL-22(interleukin22,IL-22)、IL-26(interleukin 26,IL-26)、肿瘤坏死因子(tumor necrosis factor,TNF)α等细胞因子导致机体炎症等各种疾病的发生。     

Interleukin-36 (IL-36) ligands require processing for full agonist (IL-36α, IL-36β, and IL-36γ) or antagonist (IL-36Ra) activity

IL-36α, IL-36β, and IL-36γ (formerly IL-1F6, IL-1F8, and IL-1F9) are IL-1 family members that signal through the IL-1 receptor family members IL-1Rrp2 (IL-1RL2) and IL-1RAcP. IL-36Ra (formerly IL-1F5) has been reported to antagonize IL-36γ. However, our previous attempts to demonstrate IL-36Ra antagonism were unsuccessful. Here, we demonstrate that IL-36Ra antagonist activity is dependent upon removal of its N-terminal methionine. IL-36Ra starting at Val-2 is fully active and capable of inhibiting not only IL-36γ but also IL-36α and IL-36β. Val-2 of IL-36Ra lies 9 amino acids N-terminal to an A-X-Asp motif conserved in all IL-1 family members. In further experiments, we show that truncation of IL-36α, IL-36β, and IL-36γ to this same point increased their specific activity by ～10(3)-10(4)-fold (from EC(50) 1 μg/ml to EC(50) 1 ng/ml). Inhibition of truncated IL-36β activity required ～10(2)-10(3)-fold excess IL-36Ra, similar to the ratio required for IL-1Ra to inhibit IL-1β. Chimeric receptor experiments demonstrated that the extracellular (but not cytoplasmic) domain of IL-1Rrp2 or IL-1R1 is required for inhibition by their respective natural antagonists. IL-36Ra bound to IL-1Rrp2, and pretreatment of IL-1Rrp2-expressing cells with IL-36Ra prevented IL-36β-mediated co-immunoprecipitation of IL-1Rrp2 with IL-1RAcP. Taken together, these results suggest that the mechanism of IL-36Ra antagonism is analogous to that of IL-1Ra, such that IL-36Ra binds to IL-1Rrp2 and prevents IL-1RAcP recruitment and the formation of a functional signaling complex. In addition, truncation of IL-36α, IL-36β, and IL-36γ dramatically enhances their activity, suggesting that post-translational processing is required for full activity.     

A case of myiasis in a patient with psoriasis from Turkey

Myiasis infestations caused by the larvae of flies mostly belonging to Cyclorapha suborders are frequently encountered in Turkey, which is located in the subtropical zone. The skin is a common site for myiasis, and the infestations are likely to develop in infected tissues and poorly attended wounds of the skin.

The case, a 30-year-old male patient, was diagnosed with psoriasis 18 years ago. He had psoriatic scales on his right big toe and was receiving corticosteroid and immunosuppressive drugs.

A total of 11 fly larvae were removed from the infected right first toe of the patient. Structures of the stigmas seen in the cross-sections taken from the final segments of these larvae were examined and determined as Sarcophaga spp. larvae.

Patients with infected tissues should be extremely cautious about their wound hygiene and take required fly control measures especially during summer as flies can find a suitable environment for sustenance.     

白介素家族细胞因子与干细胞动员

干细胞移植将成为或已经成为治疗多种疾病的一种重要方法,干细胞移植的成功率与干细胞增殖及扩增后干细胞的归巢能力密切相关,其过程受到许多细胞因子的调控。目前的研究发现白介素家族中的细胞因子IL1、IL2、IL3、IL4、IL6、IL7、IL8、IL9、IL10、IL11、IL12在干细胞动员过程中起到非常重要的调节作用。本文综述了这部分白介素家族成员的生物活性特征及其对干细胞动员的作用。     

Cytokines and persistent viral infections

Intracellular pathogens such as the human immunodeficiency virus, hepatitis C and B or Epstein–Barr virus often cause chronic viral infections in humans. Persistence of these viruses in the host is associated with a dramatic loss of T-cell immune response due to functional T-cell exhaustion. Developing efficient immunotherapeutic approaches to prevent viral persistence and/or to restore a highly functional T-cell mediated immunity remains a major challenge. During the last two decades, numerous studies aimed to identify relevant host-derived factors that could be modulated to achieve this goal. In this review, we focus on recent advances in our understanding of the role of cytokines in preventing or facilitating viral persistence. We concentrate on the impact of multiple relevant cytokines in T-cell dependent immune response to chronic viral infection and the potential for using cytokines as therapeutic agents in mice and humans.     

Cytokines as therapeutic targets in skin inflammation

This review focuses on treatment targets for the most common inflammatory skin diseases, eczema and psoriasis with an emphasis on cytokines expressed in the uppermost layer of the skin which is easily accessible for diagnostic and therapeutic approaches. Recently, a significant body of research has highlighted the influence of the skin barrier and the patients’ microbiome on skin inflammatory responses and we will comment on their impact on mediator regulation. Itch is a prominent dermatology symptom which is influenced by cytokines and can via itch–scratch cycle impact on the skin barrier and mediator expression associated with damage. Taking the contribution of pruritus and superficial skin damage into account, we address cytokines as targets for stratified treatment approaches in subgroups of eczema and psoriasis.