Christian M. Hedrich

Cell type-specific regulation of IL-10 expression in inflammation and disease

IL-10 plays an essential part in controlling inflammation and instructing adaptive immune responses. Consequently, dysregulation of IL-10 is linked with susceptibility to numerous infectious and autoimmune diseases in mouse models and in humans. It has become increasingly clear that appropriate temporal/spatial expression of IL-10 may be the key to how IL-10 contributes to the delicate balance between inflammation and immunoregulation. The mechanisms that govern the cell type- and receptor-specific induction of IL-10, however, remain unclear. This is due largely to the wide distribution of cellular sources that express IL-10 under diverse stimulation conditions and in a variety of tissue compartments. Further complicating the issue is the fact that human IL-10 expression patterns appear to be under genetic influence resulting in differential expression and disease susceptibility. In this review, we discuss the cellular sources of IL-10, their link to disease phenotypes and the molecular mechanisms implicated in IL-10 regulation.

Biological properties and regulation of IL-10 related cytokines and their contribution to autoimmune disease and tissue injury

The IL-10 cytokine family has nine members, four of which are located in the IL10 cluster on chromosome 1q32. These cytokines are the immune regulatory cytokine IL-10 itself, and the IL-20 subfamily members IL-19, IL-20, and IL-24. IL-10 instructs innate and adaptive immune responses and limits pro-inflammatory responses in order to prevent tissue damage. The IL-20 subfamily members are involved in host defense mechanisms, particularly from epithelial cells and seem essential for tissue integrity. Dysregulation of IL-10 family cytokines results in inflammation and autoimmune disease. Here, we discuss cellular source, gene regulation, and receptor complexes of cytokines in the IL10 cluster and their contribution to autoimmune disease and tissue damage.

Epigenetic mechanisms in systemic lupus erythematosus and other autoimmune diseases

The pathogenic origin of autoimmune diseases can be traced to both genetic susceptibility and epigenetic modifications arising from exposure to the environment. Epigenetic modifications influence gene expression and alter cellular functions without modifying the genomic sequence. CpG-DNA methylation, histone tail modifications and microRNAs (miRNAs) are the main epigenetic mechanisms of gene regulation. Understanding the molecular mechanisms that are involved in the pathophysiology of autoimmune diseases is essential for the introduction of effective, target-directed and tolerated therapies. In this review, we summarize recent findings that signify the importance of epigenetic modifications in autoimmune disorders while focusing on systemic lupus erythematosus. We also discuss future directions in basic research, autoimmune diagnostics and applied therapy.

CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance

Tissue inflammation in several autoimmune diseases, including SLE and MS, has been linked to an imbalance of IL-17-producing Th (Th17) cells and Tregs; however, the factors that promote Th17-driven autoimmunity are unclear. Here, we present evidence that the calcium/calmodulin-dependent protein kinase IV (CaMK4) is increased and required during Th17 cell differentiation. Isolation of naive T cells from a murine model of lupus revealed increased levels of CaMK4 following stimulation with Th17-inducing cytokines but not following Treg, Th1, or Th2 induction. Furthermore, naive T cells from mice lacking CaMK4 did not produce IL-17. Genetic or pharmacologic inhibition of CaMK4 decreased the frequency of IL-17-producing T cells and ameliorated EAE and lupus-like disease in murine models. Inhibition of CaMK4 reduced Il17 transcription through decreased activation of the cAMP response element modulator α (CREM-α) and reduced activation of the AKT/mTOR pathway, which is known to enhance Th17 differentiation. Importantly, silencing CaMK4 in T cells from patients with SLE and healthy individuals inhibited Th17 differentiation through reduction of IL17A and IL17F mRNA. Collectively, our results suggest that CaMK4 inhibition has potential as a therapeutic strategy for Th17-driven autoimmune diseases.

cAMP-responsive element modulator (CREM)α protein induces interleukin 17A expression and mediates epigenetic alterations at the interleukin-17A gene locus in patients with systemic lupus erythematosus.

Background: Expression levels of both IL-17A and transcription factor CREMα are increased in T cells from SLE patients. Results: In primary human T cells, CREMα binds to the proximal IL17A promoter and induces IL-17A expression by transcriptional activation and epigenetic modifications. Conclusion: CREMα promotes IL-17A expression. Significance: Suppression of CREMα expression should mitigate IL-17A-driven inflammatory responses. IL-17A is a proinflammatory cytokine that is produced by specialized T helper cells and contributes to the development of several autoimmune diseases such as systemic lupus erythematosus (SLE). Transcription factor cAMP-responsive element modulator (CREM)α displays increased expression levels in T cells from SLE patients and has been described to account for aberrant T cell function in SLE pathogenesis. In this report, we provide evidence that CREMα physically binds to a cAMP-responsive element, CRE (−111/−104), within the proximal human IL17A promoter and increases its activity. Chromatin immunoprecipitation assays reveal that activated naïve CD4+ T cells as well as T cells from SLE patients display increased CREMα binding to this site compared with T cells from healthy controls. The histone H3 modification pattern at the CRE site (−111/−104) and neighboring conserved noncoding sequences within the human IL17A gene locus suggests an accessible chromatin structure (H3K27 hypomethylation/H3K18 hyperacetylation) in activated naïve CD4+ T cells and SLE T cells. H3K27 hypomethylation is accompanied by decreased cytosine phosphate guanosine (CpG)-DNA methylation in these regions in SLE T cells. Decreased recruitment of histone deacetylase (HDAC)1 and DNA methyltransferase (DNMT)3a to the CRE site (−111/−104) probably accounts for the observed epigenetic alterations. Reporter studies confirmed that DNA methylation of the IL17A promoter indeed abrogates its inducibility. Our findings demonstrate an extended role for CREMα in the immunopathogenesis of SLE because it contributes to increased expression of IL-17A.

Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO)

Sterile bone inflammation is the hallmark of autoinflammatory bone disorders, including chronic nonbacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO). Autoinflammatory osteopathies are the result of a dysregulated innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation. Interestingly, autoinflammatory bone disorders are associated with inflammation of the skin and/or the intestine. In several monogenic autoinflammatory bone disorders mutations in disease-causing genes have been reported. However, regardless of recent developments, the molecular pathogenesis of CNO/CRMO remains unclear.Here, we discuss the clinical presentation and molecular pathophysiology of human autoinflammatory osteopathies and animal models with special focus on CNO/CRMO. Treatment options in monogenic autoinflammatory bone disorders and CRMO will be illustrated.

Stat3 promotes IL-10 expression in lupus T cells through trans-activation and chromatin remodeling.

Significance IL-10 is an immune-regulatory cytokine with pro- and anti-inflammatory functions. Through its B cell-stimulating capacities, IL-10 contributes to the differentiation, activation and survival of B cells. Thus, it has been linked with autoimmune disorders, including systemic lupus erythematosus (SLE). Here, we demonstrate T cells as a source of increased IL-10 expression in SLE. Reduced DNA methylation of the IL10 gene allows for transcription-factor recruitment. Increased phosphorylation of the transcription factor Stat3 in SLE T cells results in epigenetic remodeling and trans-activation of IL10, allowing for IL-10 expression. Thus, our observations offer molecular targets in the search for pathophysiologic mechanisms and target-directed treatment options in SLE. The immune-regulatory cytokine IL-10 plays a central role during innate and adaptive immune responses. IL-10 is elevated in the serum and tissues of patients with systemic lupus erythematosus (SLE), an autoimmune disorder characterized by autoantibody production, immune-complex formation, and altered cytokine expression. Because of its B cell-promoting effects, IL-10 may contribute to autoantibody production and tissue damage in SLE. We aimed to determine molecular events governing T cell-derived IL-10 expression in health and disease. We link reduced DNA methylation of the IL10 gene with increased recruitment of Stat family transcription factors. Stat3 and Stat5 recruitment to the IL10 promoter and an intronic enhancer regulate gene expression. Both Stat3 and Stat5 mediate trans-activation and epigenetic remodeling of IL10 through their interaction with the histone acetyltransferase p300. In T cells from SLE patients, activation of Stat3 is increased, resulting in enhanced recruitment to regulatory regions and competitive replacement of Stat5, subsequently promoting IL-10 expression. A complete understanding of the molecular events governing cytokine expression will provide new treatment options in autoimmune disorders, including SLE. The observation that altered activation of Stat3 influences IL-10 expression in T cells from SLE patients offers molecular targets in the search for novel target-directed treatment options.

Chilblain lupus erythematosus--a review of literature.

The name of one of the authors, Min Ae Lee-Kirsch, was inadvertently omitted. The full authorship of the article is as given above. Dr. Lee-Kirsch’s affiliation is as follows: (1) Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Dresden, University Hospital “Carl Gustav Carus”, Technical University Dresden, Fetscherstr. 74, 01307 Dresden, Germany Clin Rheumatol (2008) 27:1341 DOI 10.1007/s10067-008-0975-0

Stat4-dependent, T-bet-independent regulation of IL-10 in NK cells

Interleukin-10 (IL-10) is intensely studied, yet little is known about the mechanisms that control IL-10 expression. We identified striking similarities between IL-10 and interferon-γ (IFN-γ) regulation in mouse natural killer (NK) cells. Like IFN-γ, IL-10 expression is induced by IL-2 and IL-12 and IL-2+IL-12 stimulation is synergistic. Unlike IFN-γ, neither IL-18 nor Ly-49D cross-linking induced IL-10 expression however. Additionally, the IL-12 homologs IL-23 and IL-27 also do not regulate NK cell-specific IL-10. We determined that a small population of NK cells accounts for IL-10 production. The induction of IL-10 by IL-2+IL-12 treatment in NK cells appears to be biphasic, with an initial burst of expression which diminishes by 12 h but spikes again at 18 h. We determined that much like IFN-γ, Stat4 is largely required for IL-12-induced IL-10. Conversely, we observed normal induction of IL-10 in T-bet-deficient NK cells. We identified a Stat4-binding element in the fourth intron of the Il10 gene, which is completely conserved between mouse and human. This intronic Stat4 motif is within a conserved noncoding sequence, which is also a target for cytokine-induced histone acetylation. These findings highlight tissue- and receptor-specific IL-10 regulatory mechanisms, which may be part of an early feedback loop.

cAMP-responsive Element Modulator (CREM)α Protein Signaling Mediates Epigenetic Remodeling of the Human Interleukin-2 Gene: IMPLICATIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS*

Background: IL-2 expression is suppressed in SLE T lymphocytes. Results: CREMα binding to IL2 mediates histone H3K18 deacetylation through HDAC1 and CpG-DNA methylation through DNMT3a. Conclusion: CREMα mediates epigenetic remodeling of IL2 in SLE T cells. Significance: Understanding the molecular mechanisms that cause cytokine imbalances in SLE will help to establish target-directed therapeutic approaches. IL-2 is a key cytokine during proliferation and activation of T lymphocytes and functions as an auto- and paracrine growth factor. Regardless of activating effects on T lymphocytes, the absence of IL-2 has been linked to the development of autoimmune pathology in mice and humans. Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease and characterized by dysregulation of lymphocyte function, transcription factor and cytokine expression, and antigen presentation. Reduced IL-2 expression is a hallmark of SLE T lymphocytes and results in decreased numbers of regulatory T lymphocytes which play an important role in preventing autoimmunity. Reduced IL-2 expression was linked to overproduction of the transcription regulatory factor cAMP-responsive element modulator (CREM)α in SLE T lymphocytes and subsequent CREMα binding to a CRE site within the IL2 promoter (−180 CRE). In this study, we demonstrate the involvement of CREMα-mediated IL2 silencing in T lymphocytes from SLE patients through a gene-wide histone deacetylase 1-directed deacetylation of histone H3K18 and DNA methyltransferase 3a-directed cytosine phosphate guanosine (CpG)-DNA hypermethylation. For the first time, we provide direct evidence that CREMα mediates silencing of the IL2 gene in SLE T cells though histone deacetylation and CpG-DNA methylation.