Frederick, MD, United States
Frederick, MD, United States

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Munoz M.,Charité - Medical University of Berlin | Munoz M.,Laboratory of Experimental Immunology | Munoz M.,Leibniz Institute | Eidenschenk C.,Genentech | And 16 more authors.
Immunity | Year: 2015

T helper 1 (Th1) cell-associated immunity exacerbates ileitis induced by oral Toxoplasma gondii infection. We show here that attenuated ileitis observed ininterleukin-22 (IL-22)-deficient mice was associated with reduced production of Th1-cell-promoting IL-18. IL-22 not only augmented the expression of Il18 mRNA and inactive precursor protein (proIL-18) in intestinal epithelial cells after T.gondii or Citrobacter rodentium infection, but also maintained the homeostatic amount of proIL-18 in the ileum. IL-22, however, did not induce the processing to active IL-18, suggesting a two-step regulation of IL-18 inthese cells. Although IL-18 exerted pathogenic functions during ileitis triggered by T.gondii, it was required for host defense against C.rodentium. Conversely, IL-18 was required for the expression of IL-22 in innate lymphoid cells (ILCs) upon T.gondii infection. Our results define IL-18 as an IL-22 target gene in epithelial cells and describe a complex mutual regulation of both cytokines during intestinal infection. © 2015 Elsevier Inc.


Gamero A.M.,Laboratory of Experimental Immunology | Young M.R.,U.S. National Cancer Institute | Mentor-Marcel R.,U.S. National Cancer Institute | Bobe G.,U.S. National Cancer Institute | And 3 more authors.
Cancer Prevention Research | Year: 2010

Signal transducer and activator of transcription 2 (STAT2) is an essential transcription factor in the type I IFN (IFN-α/β) signal transduction pathway and known for its role in mediating antiviral immunity and cell growth inhibition. Unlike other members of the STAT family, IFNs are the only cytokines known to date that can activate STAT2. Given the inflammatory and antiproliferative dual nature of IFNs, we hypothesized that STAT2 prevents inflammation-induced colorectal and skin carcinogenesis by altering the inflammatory immune response. Contrary to our hypothesis, deletion of STAT2 inhibited azoxymethane/dextran sodium sulfate-induced colorectal carcinogenesis as measured by prolonged survival, lower adenoma incidence, smaller polyps, and less chronic inflammation. STAT2 deficiency also inhibited 7,12-dimethylbenz(a) anthracene/12-O-tetradecanoylphorbol-13-acetate-induced skin carcinogenesis as indicated by reduced papilloma multiplicity. A potential mechanism by which STAT2 promotes carcinogenesis is through activation of proinflammatory mediators. Deletion of STAT2 decreased azoxymethane/dextran sodium sulfate-induced expression and release of proinflammatory mediators, such as interleukin-6 and CCL2, and decreased interleukin-6 release from skin carcinoma cells, which then decreased STAT3 activation. Our findings identify STAT2 as a novel contributor to colorectal and skin carcinogenesis that may act to increase the gene expression and secretion of proinflammatory mediators, which in turn activate the oncogenic STAT3 signaling pathway. © 2010 American Association for Cancer Research.


Pennino D.,Helmholtz Center Munich | Pennino D.,Imperial College London | Bhavsar P.K.,Imperial College London | Effner R.,Helmholtz Center Munich | And 12 more authors.
Journal of Allergy and Clinical Immunology | Year: 2013

Background: IL-22 controls tissue homeostasis by both proinflammatory and anti-inflammatory effects. However, the anti-inflammatory mechanisms of IL-22 remain poorly investigated. Objective: We sought to investigate the anti-inflammatory role for IL-22 in human asthma. Methods: T-cell lines derived from lung biopsy specimens of asthmatic patients were characterized by means of flow cytometry. Human bronchial epithelial cells from healthy and asthmatic subjects were stimulated with IL-22, IFN-γ, or the combination of both cytokines. Effects of cytokine stimulation were investigated by using whole-genome analysis, ELISA, and flow cytometry. The functional consequence of cytokine stimulation was evaluated in an in vitro wound repair model and T cell-mediated cytotoxicity experiments. In vivo cytokine expression was measured by using immunohistochemistry and Luminex assays in bronchoalveolar lavage fluid of healthy and asthmatic patients. Results: The current study identifies a tissue-restricted antagonistic interplay of IL-22 and the proinflammatory cytokine IFN-γ. On the one hand, IFN-γ antagonized IL-22-mediated induction of the antimicrobial peptide S100A7 and epithelial cell migration in bronchial epithelial cells. On the other hand, IL-22 decreased epithelial susceptibility to T cell-mediated cytotoxicity by inhibiting the IFN-γ-induced expression of MHC-I, MHC-II, and CD54/intercellular adhesion molecule 1 molecules. Likewise, IL-22 inhibited IFN-γ-induced secretion of the proinflammatory chemokines CCL5/RANTES and CXCL10/interferon-inducible protein 10 in vitro. Consistently, the IL-22 expression in bronchoalveolar lavage fluid of asthmatic patients inversely correlated with the expression of CCL5/RANTES and CXCL10/interferon-inducible protein 10 in vivo. Conclusions: IL-22 might control the extent of IFN-γ-mediated lung inflammation and therefore play a tissue-restricted regulatory role. © 2012 American Academy of Allergy, Asthma & Immunology.


Cavani A.,Laboratory of Experimental Immunology | Pennino D.,Helmholtz Center Munich | Eyerich K.,Helmholtz Center Munich
Chemical Immunology and Allergy | Year: 2012

Development of eczematous skin reactions depends on disease-specific and time-dependent recruitment of a variety of leukocytes affecting resident skin cells through cytotoxic mechanisms and release of cytokines. Th17 and Th22, defined as RORC+IL-17+ and IL-17-IFN-γ-IL-22+ cells, respectively, belong to a newly identified class of lymphocytes specifically involved in dialogue with non-immune cells. In line with this function, both Th17 and Th22 cells are enriched in many immune-mediated skin diseases, such as a topic dermatitis, allergic contact dermatitis and psoriasis. Both IL-17 and IL-22 activate keratinocyte innate immune defenses, thus protecting the skin from pathogen invasion. However, Th17 and Th22 differ in their proinflammatory functions, being prominent in the first T cell subset and occasional/opportunistic in the second T cell subset. Most of the proinflammatory functions of Th17 depend on the synergic activity of IFN-γ and IL-17 on target cells. Together with IFN-γ, IL-17 strongly enhances adhesion molecules on keratinocytes, thus promoting T cell-keratinocyte adhesion and T cell-mediated cytotoxicity, resulting in keratinocyte apoptosis. In contrast, Th22 cells guarantee skin integrity by inducing keratinocyte proliferation and migration. However, in inflamed skin, Th22 could contribute to the amplification of immune responses by enhancing the TNF-α-induced cytokines and chemokines released by keratinocytes. © 2012 S. Karger AG, Basel.


Pastore S.,Laboratory of Experimental Immunology | Lulli D.,Laboratory of Experimental Immunology | Girolomoni G.,University of Verona
Archives of Toxicology | Year: 2014

The epidermal growth factor receptor (EGFR) and its ligands have been long recognized as centrally involved in the growth and repair process of epithelia, as well as in carcinogenesis. In addition, the EGFR has been demonstrated to be importantly involved in the control of inflammatory responses. During this last decade, a number of highly specific agents targeting this system have become an integral component of pharmacologic strategies against many solid malignancies. These drugs have led to increased patient survival and made therapy more tolerant when compared to conventional cytotoxic drugs. Nonetheless, their use is associated with a constellation of toxic effects on the skin, including follicular pustules, persistent inflammation, xerosis and pruritus, and enhanced susceptibility to infections. This dramatic impairment of skin homoeostasis underscores the centrality of the EGFR-ligand system in the whole skin immune system. So far, no mechanism-based approaches are available to specifically counteract the adverse effects of anti-EGFR drugs or any other class of tyrosine kinase inhibitors. Only the knowledge of the cellular and molecular events underlying these adverse effects in humans, combined with in vitro/in vivo models able to mimic these toxic responses, may guide the development of mechanism-based treatment or prevention strategies. © 2014 Springer-Verlag.


Chang J.,Harvard University | Lindsay R.J.,Harvard University | Kulkarni S.,Laboratory of Experimental Immunology | Lifson J.D.,SAIC | And 3 more authors.
AIDS | Year: 2011

Recognition of HIV-1 ssRNA by Toll-like receptor 7 induces the production of the pro-inflammatory cytokines that may contribute to the systemic immune activation associated with HIV-1 disease progression. Here, we describe a novel association between polymorphisms in interferon regulatory factor 7 (IRF7), a master regulator of interferon-α (IFN-α), and the ability of plasmacytoid dendritic cells to produce IFN-α in response to HIV-1. IRF7 polymorphisms may, therefore, affect the ability of individuals to respond to HIV-1 and modulate HIV-1 disease progression. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Cavani A.,Laboratory of Experimental Immunology | De Luca A.,Laboratory of Experimental Immunology
Current Drug Metabolism | Year: 2010

Allergic contact dermatitis is a common eczematous skin disease that occurs in sensitized individuals at the site of contact with small chemicals penetrating the skin barrier. The onset of the disease is mostly due to the rapid recruitment of chemical-specific CD8+ T cells, which induce apoptosis of keratinocytes. Additionally, CD4+ Th1 and Th17 contribute to the extension of the inflammatory reaction by releasing pro-inflammatory cytokines that activate keratinocytes and other skin resident cells. The immune reaction is tightly regulated through multiple mechanisms. In particular, T cell population with regulatory function, such as T regulatory cells 1 and CD4+CD25+ T regulatory cells have a critical role in preventing the development of allergic reactions to innocuous chemicals contacting the skin, and in limiting the magnitude of the inflammatory process in already sensitized individuals. Allergic contact dermatitis is a chronic disease, which lasts, in most cases, for the entire life of the affected individual. Thus, prevention and avoidance of contact with the sensitizer are critical factors in the management of affected patients. The gold standard therapeutic approach for the disease remains the local and/or systemic immunosuppression, aimed to block T cell functions and keratinocyte responsiveness to pro-inflammatory stimuli. However, alternative approaches that aim at preventing T cell accumulation in peripheral tissues are under investigation. Most recently, disclosure of mechanisms regulating allergic contact dermatitis have provided new therapeutic perspectives for the disease, mostly based on immunomodulatory interventions, as in the case of induction of specific oral tolerance to the causative allergen. © 2010 Bentham Science Publishers Ltd.


Lulli D.,Laboratory of Experimental Immunology | Carbone M.L.,Laboratory of Experimental Immunology | Pastore S.,Laboratory of Experimental Immunology
Oncotarget | Year: 2016

The Epidermal Growth Factor Receptor (EGFR) is centrally involved in the regulation of key processes of the epithelia, including cell proliferation, survival, differentiation, and also tumorigenesis. Humanized antibodies and small-molecule inhibitors targeting EGFR were developed to disrupt these functions in cancer cells and are currently used in the treatment of diverse metastatic epithelial cancers. By contrast, these drugs possess significant skin-specific toxic effects, comprising the establishment of a persistent inflammatory milieu. So far, the molecular mechanisms underlying these epiphenomena have been investigated rather poorly. Here we showed that keratinocytes respond to anti-EGFR drugs with the development of a type I interferon molecular signature. Upregulation of the transcription factor IRF1 is early implicated in the enhanced expression of interferon-kappa, leading to persistent activation of STAT1 and further amplification of downstream interferoninduced genes, including anti-viral effectors and chemokines. When anti-EGFR drugs are associated to TNF-a, whose expression is enhanced by the drugs themselves, all these molecular events undergo a dramatic enhancement by synergy mechanisms. Finally, high levels of interferon-kappa can be observed in epidermal keratinocytes and also in leukocytes infiltrating the upper dermis of cetuximab-driven skin lesions. Our data suggest that dysregulated activation of type I interferon innate immunity is implicated in the molecular processes triggered by anti-EGFR drugs and leading to persistent skin inflammation.


Moitra K.,Laboratory of Experimental Immunology | Lou H.,SAIC | Dean M.,Laboratory of Experimental Immunology
Clinical Pharmacology and Therapeutics | Year: 2011

Stem cells possess the dual properties of self-renewal and pluripotency. Self-renewal affords these populations the luxury of self-propagation, whereas pluripotency allows them to produce the multitude of cell types found in the body. Protection of the stem cell population from damage or death is critical because these cells need to remain intact throughout the life of an organism. The principal mechanism of protection is through expression of multifunctional efflux transportersthe adenosine triphosphate-binding cassette (ABC) transporters that are the guardians of the stem cell population. Ironically, it has been shown that these ABC efflux pumps also afford protection to cancer stem cells (CSCs), shielding them from the adverse effects of chemotherapeutic insult. It is therefore imperative to gain a better understanding of the mechanisms involved in the resistance of stem cells to chemotherapy, which could lead to the discovery of new therapeutic targets and improvement of current anticancer strategies. © 2011 ASCPT.


Moitra K.,Laboratory of Experimental Immunology | Dean M.,Laboratory of Experimental Immunology
Biological Chemistry | Year: 2011

The ATP-binding cassette (ABC) transporter genes represent the largest family of transporters and these genes are abundant in the genome of all vertebrates. Through analysis of the genome sequence databases we have characterized the full complement of ABC genes from several mammals and other vertebrates. Multiple gene duplication and deletion events were identified in ABC genes in different lineages indicating that the process of gene evolution is still ongoing. Gene duplication resulting in either gene birth or gene death plays a major role in the evolution of the vertebrate ABC genes. The understanding of this mechanism is important in the context of human health because these ABC genes are associated with human disease, involving nearly all organ systems of the body. In addition, ABC genes play an important role in the development of drug resistance in cancer cells. Future genetic, functional, and evolutionary studies of ABC transporters will provide important insight into human and animal biology. © 2011 by Walter de Gruyter Berlin New York.

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