Acute and chronic models of allergic contact dermatitis: advantages and limitations.
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Acute Disease↗
Biomedical subjects
K Asadullah
Publications and source records attributed to K Asadullah.
Is there an interaction between interleukin-10 and interleukin-22?
Interleukin(IL)-10 and IL-22 are structurally related cytokines. Their heterodimeric receptors consist of the cytokine-specific chains IL-10R1 and IL-22R1, respectively, and the common chain IL-10R2. This study focused on the question of whether IL-10 modulates IL-22 effects and vice versa. This question is important because IL-10 and IL-22 exert anti- and proinflammatory effects, respectively, and, as we show here, are simultaneously present in both systemic and local inflammation. The revealed lacking concomitance of IL-10R1 and IL-22R1 on identical cells excluded any possible interaction between IL-10 and IL-22 apart from the competition for IL-10R2. To study this competition, monocytes and hepatocytes were chosen. The dependence of the cytokine action on IL-10R2 was verified. Interestingly, no influence of IL-22 on IL-10 effects was observed. The same was true when IL-22 was used in complex with IL-22-binding protein. Similarly, no influence of IL-10 was found on IL-22 action. This missing competition seemed to be due to a lack of binding between IL-10R2 and the native cytokines in the absence of their corresponding R1 chain. However, IL-10R2 interacted with defined IL-10- and IL-22-derived peptides supporting the hypothesis that cytokine binding to its corresponding R1 chain creates a binding site on this cytokine for IL-10R2.
Animals↗
Cloning of murine IL-22 receptor alpha 2 and comparison with its human counterpart.
We have identified the mouse and rat homologs of human interleukin-22 receptor alpha 2 (IL-22R alpha 2) and compared the localization, structure, and expression of the encoding murine and human genes. The mouse IL-22R alpha 2-encoding gene is located on chromosome 10A3 between, like in human, the genes for interferon-gamma R1 and IL-20R1. It spans a region of approximately 10 kb therefore being three times shorter than the human gene. Although the overall gene structure in both species is similar, the mouse gene lacks a counterpart to the third coding exon of the human gene known to be alternatively spliced. Like in human, mouse and rat IL-22R alpha 2 exist only as soluble receptors as deduced from the lack of transmembrane and intracellular domains encoding sequences. Quantitative expression analyses showed, analogically to the human system, a limited tissue distribution of mouse IL-22R alpha 2 mRNA. Differential modulation of IL-22R alpha 2 mRNA expression was observed upon systemic inflammation in mice in spleen, thymus, and lymph node.
Amino Acid Sequence↗
Molecular mechanisms of interleukin-10-mediated inhibition of NF-kappaB activity: a role for p50.
Nuclear factor kappa B (NF-kappaB) is a transcription factor pivotal for the development of inflammation. A dysregulation of NF-kappaB has been shown to play an important role in many chronic inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and psoriasis. Although classical NF-kappaB, a heterodimer composed of the p50 and p65 subunits, has been well studied, little is known about gene regulation by other hetero- and homodimeric forms of NF-kappaB. While p65 possesses a transactivation domain, p50 does not. Indeed, p50/p50 homodimers have been shown to inhibit transcriptional activity. We have recently shown that Interleukin-10 exerts its anti-inflammatory activity in part through the inhibition of NF-kappaB by blocking IkappaB kinase activity and by inhibiting NF-kappaB already found in the nucleus. Since the inhibition of nuclear NF-kappaB could not be explained by an increase of nuclear IkappaB, we sought to further investigate the mechanisms involved in the inhibition of NF-kappaB by IL-10. We show here that IL-10 selectively induced nuclear translocation and DNA-binding of p50/p50 homodimers in human monocytic cells. TNF-alpha treatment led to a strong translocation of p65 and p50, whereas pretreatment with IL-10 followed by TNF-alpha blocked p65 translocation but did not alter the strong translocation of p50. Furthermore, macrophages of p105/p50-deficient mice exhibited a significantly decreased constitutive production of MIP-2alpha and IL-6 in comparison to wild type controls. Surprisingly, IL-10 inhibited high constitutive levels of these cytokines in wt macrophages but not in p105/p50 deficient cells. Our findings suggest that the selective induction of nuclear translocation and DNA-binding of the repressive p50/p50 homodimer is an important anti-inflammatory mechanism utilized by IL-10 to repress inflammatory gene transcription.
Animals↗
[Use of biologicals in psoriasis].
With a prevalence of 2-3 percent, psoriasis is one of the most common diseases in dermatology. Most patients can be treated sufficiently with topical emollients, but approximately 20 percent of all patients suffering from psoriasis need photo- and/or systemic therapies. Side effects, contraindications, insufficient clinical responses, and lack of long-term efficacy underline the need for novel and improved antipsoriatic therapies. Several biologics interfering with key steps in the immunopathogenesis of psoriasis bear the potential to meet this need with regard to treating moderate to severe psoriasis. Progress made in the understanding of the pathophysiology of psoriasis as T-cell mediated dermatosis does provide options for new, more precise therapeutic approaches. These immunological therapeutic strategies are targeted at the inhibition of T-cell activation, the depletion of activated T-lymphocytes, the inhibition of adhesion of inflammatory cells, the inhibition of effects of proinflammatory cytokines and the application of antiinflammatory cytokines. This article gives a summary of new biologicals used in the treatment of psoriasis. Clinical results received from first applications are inconclusive. Further results of the studies from phase II and phase III can be expected in the next few years, which should make it possible to achieve better assessments of the potential of these types of treatments. Some of these approaches could lead to the approval of new drugs to treat psoriasis and to enhance or replace already existing therapeutic options.
Anti-Inflammatory Agents↗
Subclinical activation of latent cytomegalovirus (CMV) infection and anti-CMV immune response in patients with atopic dermatitis.
BACKGROUND: Microbiological infections are considered to be of pathophysiological importance in atopic dermatitis (AD). As yet, no information is available regarding cytomegalovirus (CMV) infection in this disease. This, however, is of interest because of the high prevalence of latent infections in the general population, the frequent reactivation in inflammatory diseases, and the immunomodulating capacity of CMV. OBJECTIVES: To investigate the prevalence of latent CMV infection, the frequency of active CMV infection, and the immune response to CMV in patients with moderate to severe AD. Methods To detect active infection we analysed CMV antigen expression by peripheral blood mononuclear cells (PBMC) from 27 patients with moderate to severe AD in comparison with 53 healthy volunteers. We used three monoclonal antibodies recognizing different CMV-encoded antigens and immunocytological staining (alkaline phosphatase-antialkaline phosphatase technique). RESULTS: Patients with AD had a higher mean frequency of CMV-positive PBMC: 2.25 per 10 000 vs. 0.74 per 10 000 in controls (P = 0.001) as well as a higher incidence of CMV antigenaemia: 29.6% vs. 7.5% (P < 0.01). Seropositivity for anti-CMV IgG antibodies indicated subclinical activation of latent infection. Remarkably, a clearance of CMV antigenaemia was observed during anti-eczematous treatment. Significantly higher plasma levels of tumour necrosis factor-alpha, which is involved in CMV reactivation, and interleukin-12, which is crucial for an antiviral cellular immune response, were observed in AD patients in comparison with healthy volunteers. Furthermore, a significantly enhanced frequency of circulating activated HLA-DR+ T cells especially in CMV-seropositive AD patients (19.3% vs. 13.5% in seronegative AD patients vs. 10.2% in controls) suggested that the active CMV infection triggers a cellular immune response. This was also supported by a high frequency of CMV-specific interferon-gamma-producing T cells in CMV-seropositive patients with AD. CONCLUSIONS: Our data suggest that active, subclinical CMV infection is more frequent in patients with moderate to severe AD and may have immunopathophysiological relevance.
Adult↗
Interleukin-10 promoter polymorphism IL10.G and familial early onset psoriasis.
BACKGROUND: The anti-inflammatory cytokine interleukin (IL)-10 is considered to play a major role in the pathophysiology of psoriasis, which is characterized by an IL-10 deficiency. Systemic administration of IL-10 has been shown to be an effective therapy for psoriasis. The IL-10 promoter region contains a highly polymorphic microsatellite (IL10.G) and in a recent case-control study the IL10.G13 (144 bp) allele was found to be associated with familial early onset psoriasis (type 1 psoriasis) having a susceptible effect. OBJECTIVES: As it is essential in multifactorial diseases to replicate findings before definite conclusions can be drawn, we decided to perform a follow-up study and to follow a genetic approach analysing allele transmission in families with a positive family history of psoriasis. METHODS: We studied 137 nuclear families (trio-design) comprising 456 individuals and genotyped the IL10.G marker. For comparison we also genotyped the microsatellite tn62 as a reference marker of the major psoriasis susceptibility locus on chromosome 6p21 (PSORS1). In the present study allele transmission was evaluated using the family-based association test (FBAT) and GENEHUNTER 2.0 based on the transmission/disequilibrium test. RESULTS: The G13 allele (144 bp) had a frequency of 24%, was present in 88 families and clearly showed an even transmission (FBAT, P = 0.753). In contrast, allele 3 (IL10.G9) (136 bp) had a frequency of 39%, was present in 110 families and was transmitted in 43 trios and remained untransmitted in 67 trios (FBAT, P = 0.026), thus showing preferential nontransmission. For the HLA-linked tn62-marker we obtained a P-value of 0.00027 for allele 4 in the same study group. CONCLUSIONS: In conclusion, we failed to confirm the susceptible effect of the G13 allele, but provide the first data for a protective effect of allele 3 (IL10.G9) for familial psoriasis. Our results suggest that the IL10.G polymorphism is not a major locus, but acts as a minor locus.
Alleles↗
Interleukin-10 therapy--review of a new approach.
Interleukin (IL)-10 is an important immunoregulatory cytokine produced by many cell populations. Its main biological function seems to be the limitation and termination of inflammatory responses and the regulation of differentiation and proliferation of several immune cells such as T cells, B cells, natural killer cells, antigen-presenting cells, mast cells, and granulocytes. However, very recent data suggest IL-10 also mediates immunostimulatory properties that help to eliminate infectious and noninfectious particles with limited inflammation. Numerous investigations, including expression analyses in patients, in vitro and animal experiments suggest a major impact of IL-10 in inflammatory, malignant, and autoimmune diseases. So IL-10 overexpression was found in certain tumors as melanoma and several lymphomas and is considered to promote further tumor development. Systemic IL-10 release is a powerful tool of the central nervous system to prevent hyperinflammatory processes by activation of the neuro-endocrine axis following acute stress reactions. In contrast, a relative IL-10 deficiency has been observed and is regarded to be of pathophysiological relevance in certain inflammatory disorders characterized by a type 1 cytokine pattern such as psoriasis. Recombinant human IL-10 has been produced and is currently being tested in clinical trials. This includes rheumatoid arthritis, inflammatory bowel disease, psoriasis, organ transplantation, and chronic hepatitis C. The results are heterogeneous. They give new insight into the immunobiology of IL-10 and suggest that the IL-10/IL-10 receptor system may become a new therapeutic target.
Animals↗
SEGRAs: a novel class of anti-inflammatory compounds.
Dissociated GCs show a separation between anti-inflammatory effects and certain side effects. This renders them as attractive compounds with better effect/side-effect profile as promising drug candidates and tool compounds for analyzing the molecular mechanisms of single side effects. A number of the GC-mediated side effects (e.g., osteoporosis, skin atrophy) are regulated in a very complex manner and use more than one molecular mechanism of the GR. Thus, theoretical predictions about the behavior of selective GR agonists regarding these effects are very difficult to make. Investigations of SEGRA compounds in relevant animal models will be the only way to get this important information. By availability of these tool compounds we now are in the advantageous situation to test them in vivo and to learn more about the possibilities and even the limitations of the selective GR agonists. Considering that the compounds have a non-steroidal structure, i.e., totally unrelated to steroids or other hormones at all, displaying only partially the molecular effects of GCs and are dissociated in their clinical profile, they should not be considered as GCs. Therefore, we introduced the term selective glucocorticoid receptor agonists (SEGRAs). These SEGRAs seem to represent a useful novel therapeutic modality which may complement existing therapeutic principles for the topical and especially the systemic treatment of inflammatory diseases. In summary, we and others are convinced that dissociated GCs are therapeutic compounds that exert many of the anti-inflammatory and immunosuppressive effects of standard GCs, while their potential to induce side effects is reduced. Whereas the in vitro dissociated profile of other compound classes (Belvisi et al. 2001) was not translated into a separation between anti-inflammatory activity and the induction of side effects in in vivo models, we could demonstrate this for the SEGRA compounds. Regarding the diversity of molecular mechanisms involved in mediating the complex side effects of GCs, it might be that only some of these unwanted effects can be reduced. However, as GCs are one of the most important anti-inflammatory therapeutics in the treatment of severe and chronic inflammatory diseases, even a partial reduction of side effect induction would be a great advantage for many patients.
Administration, Topical↗
Topical glucocorticoid therapy in dermatology.
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Administration, Topical↗
Cytokine therapy in dermatology.
Cytokines have been in the focus of scientific interest for some years now. Analysing their expression permitted a better understanding of the pathogenesis of various diseases, including in dermatology. Moreover, they are now far beyond the stage when they were of interest only to the pathophysiological research sector: some cytokine therapies are already being employed as part of the clinical practice. In fact, several cytokines are used for the treatment of malignant, inflammatory and infectious skin diseases. Their stage of development ranges from advanced, already approved and well established therapies (e.g. IFN-alpha and IL-2 for melanoma) to early explorative trials (e.g. IL-4 and IL-10 for psoriasis). Some of the new approaches currently under investigation will actually lead to registration of new drugs for dermatological treatment and to supplement existing therapeutic options. Beside this, the results of clinical trials with cytokines are significantly contributing to our understanding of the pathophysiology of diseases. They will give a better insight into which mechanisms play a greater or lesser part in their development and may generate momentum for still better targeted pharmacological approaches. Here we would like to give an overview about the current stage of cytokine therapy and the prospects for dermatological indications. The terminology and immunobiology of cytokines are also briefly discussed, since for a sensible interpretation of the relevant findings a basic knowledge of these biologically highly active messenger substances is essential.
Chronic Disease↗
Cytokines: interleukin and interferon therapy in dermatology.
Cytokines are highly potent biologically active proteins that play an essential role in intercellular communication. They are vital to the mediation and regulation of inflammatory and specific immune reactions as well as to nonimmunological processes. Several cytokines are already used for the treatment of malignant, inflammatory and infectious skin diseases. This in particular includes certain interleukins (ILs) and interferons (IFNs). Whereas some cytokine therapies are already approved and well established, such as IFN-alpha and IL-2 (approved in the USA) for melanoma, others are in the early stages of development and are used in explorative trials (e.g. IL-4 and IL-10 in the treatment of psoriasis). It is likely that some of the new approaches currently under investigation will actually lead to both the registration of new drugs for dermatological treatment, and to supplementation of existing therapeutic options. The aim of this review is to give an overview on the current state of cytokine therapy in dermatology.
Antineoplastic Agents↗
IL-10 and its homologs: important immune mediators and emerging immunotherapeutic targets.
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Animals↗
A novel, soluble homologue of the human IL-10 receptor with preferential expression in placenta.
The cytokine receptor family type 2 (CRF2) comprises receptors for important immunomediators like interferons and interleukin-10 (IL-10). We identified a novel member of this family which represents the first exclusively soluble receptor in this group and was therefore designated as CRF2-soluble 1 (CRF2-s1). The CRF2-s1 gene covers about 28 kb and is located on chromosome 6 in close proximity to the CRF2 members interferon (IFN)-gamma receptor 1 and IL-20 receptor 1. It comprises seven exons and generates two different mRNA splice variants, CRF2-s1-long and CRF2-s1-short. CRF2-s1-long and CRF2-s1-short encode proteins of 263 and 231 amino acids, respectively. A comparison of predicted protein structures led to the postulation that each receptor variants binds a different ligand. Quantitative analysis of human mRNA expression revealed a very restricted pattern for both splice forms. CRF2-s1 turned out to be the first member of this receptor family which was expressed neither in resting nor in stimulated leucocyte populations. CRF2-s1-long was only expressed in placenta, whereas CRF2-s1-short was additionally expressed in human mammary gland and, at a lower level, in skin, spleen, thymus and stomach. The preferential expression of CRF2-s1 in placenta suggests a role for this receptor in establishing and maintaining successful pregnancy.
Amino Acid Sequence↗
Effects of systemic interleukin-10 therapy on psoriatic skin lesions: histologic, immunohistologic, and molecular biology findings.
Interleukin-10 is an important anti-inflammatory and immunosuppressive cytokine with major impact on several immune reactions, including regulatory mechanisms in the skin. Recently, we performed a phase II trial in psoriatic patients receiving subcutaneously interleukin-10 over 7 wk. The clinical response suggested that interleukin-10 might represent a novel anti-psoriatic drug. In order to understand better the mode of action and to elucidate the effects of systemic interleukin-10 treatment on the skin immune system, skin punch biopsies from sites different from interleukin-10 injection were analyzed. Biopsies were obtained from the patients before, at the end, and 3 wk after interleukin-10 therapy. The results are reported here. Histologic examination showed a decrease of several parameters reflecting the psoriatic disease activity as acanthosis and extension of the horny layer. Immunohistologic examination demonstrated decreasing numbers of infiltrating T cells, dermal CD1a+ cells, and a diminished proliferation of epidermal cells. Using a novel, quantitative reverse transcriptase-polymerase chain reaction approach a significant shift within the cytokine pattern was found. Interleukin-10 therapy led to a decrease of cutaneous interleukin-8 and interleukin-10 mRNA expression. Whereas no significant changes of interleukin-6, tumor necrosis factor-alpha, and interferon-gamma expression were found, interleukin-4 was strongly upregulated suggesting a shift from a type 1 towards a type 2 cytokine pattern. The changes within the local cytokine pattern seem to be disease-related, as an inverse course was found in a single interleukin-10 nonresponding patient. Our findings demonstrate considerable effects of systemic interleukin-10 application on the skin immune systems, which might contribute to the anti-psoriatic activity of interleukin-10.
Adult↗
Interleukin-10 promoter polymorphism in psoriasis.
Beneficial effects of interleukin-10 therapy and lower endogenous interleukin-10 formation compared with atopic dermatitis and cutaneous T cell lymphomas indicated that interleukin-10 is a key cytokine in psoriasis. The interleukin-10 promoter is highly polymorphic, with two informative microsatellites, interleukin-10.G and interleukin-10.R. In order to understand whether interleukin-10 itself is a predisposing gene for the psoriasis susceptibility we analyzed interleukin-10 promotor polymorphism in patients. The distribution of interleukin-10.G and interleukin10.R microsatellite alleles did not vary between patients (n = 78) and healthy controls (n = 80). In addition, when the psoriasis patients were stratified according to age of onset (younger than 40 y of age, or age 40 and older), no difference in allele distribution was observed; however, a clear differential distribution was revealed at the interleukin10.G locus when patients were stratified according to whether they had a positive family history of psoriasis (p = 0.04). This difference was due to an over-representation of the interleukin10.G13 allele in those patients with familial disease (40.4% vs 19.6%, Chi-square = 7.292, p = 0.007). The positive association of allele interleukin10.G13 with familial psoriasis was especially true when patients with an early onset (< 40 y of age) of the disease were compared with those patients with early onset against a nonfamilial background (39.6% vs 14.5%, Chi-square = 8.959, p = 0.003). Patients with age-of-onset of less than 40 were 4-fold [odds ratio = 3.85 (1.55--9.62)] more likely to have a psoriatic family background if they carried this interleukin10.G13 allele. These data suggest that the interleukin-10 locus contributes to the heritability of psoriasis susceptibility.
Alleles↗
Inhibition of keratinocyte apoptosis by IL-15: a new parameter in the pathogenesis of psoriasis?
Keratinocytes (KC) are important source of and targets for several cytokines. Although KC express IL-15 mRNA, the functional effects of IL-15 on these epithelial cells remain to be dissected. Investigating primary human foreskin KC and HaCaT cells, we show here by semiquantitative RT-PCR and flow cytometric analysis that both translate IL-15 and IL-15R mRNA and express IL-15 and IL-15Ralpha protein on the cell surface, suggesting that human KC can employ IL-15 for juxtacrine signaling. While IL-15 exerted no significant effect on KC proliferation and IL-6 or IL-8 secretion, IL-15 inhibited both anti-Fas and methylcellulose-induced KC apoptosis in vitro. This is in line with the recognized potent anti-apoptotic effects of IL-15. IL-2, whose receptor shares two components with the IL-15R, failed to inhibit KC apoptosis. Together with the role of IL-15 in sustaining chronic immune reactions, this invited the question of whether a reduction of KC apoptosis by IL-15 may be involved in the pathogenesis of psoriasis, a chronic hyperproliferative inflammatory skin disease characterized by abnormally low KC apoptosis in the epidermis. Remarkably, compared with nonlesional psoriatic skin and skin of healthy volunteers, lesional psoriatic epidermis showed high IL-15 protein expression in the epidermis and enhanced binding activity for IL-15. Therefore, antagonizing the inhibitory effects of IL-15 on KC apoptosis deserves exploration as a novel therapeutic strategy in psoriasis management.
Apoptosis↗
Flow cytometric characterization of lesional T cells in psoriasis: intracellular cytokine and surface antigen expression indicates an activated, memory/effector type 1 immunophenotype.
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Adult↗