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1.
J Biol Chem ; 292(7): 2805-2814, 2017 02 17.
Article in English | MEDLINE | ID: mdl-28057759

ABSTRACT

There is experimental and clinical evidence that some exanthematous allergic drug hypersensitivity reactions are mediated by drug-specific T cells. We hypothesized that the capacity of certain drugs to directly stimulate the innate immune system may contribute to generate drug-specific T cells. Here we analyzed whether abacavir, an HIV-1 reverse transcriptase inhibitor often inducing severe delayed-type drug hypersensitivity, can trigger innate immune activation that may contribute to its allergic potential. We show that abacavir fails to generate direct innate immune activation in human monocytes but potently triggers IL-1ß release upon pro-inflammatory priming with phorbol ester or Toll-like receptor stimulation. IL-1ß processing and secretion were sensitive to Caspase-1 inhibition, NLRP3 knockdown, and K+ efflux inhibition and were not observed with other non-allergenic nucleoside reverse transcriptase inhibitors, identifying abacavir as a specific inflammasome activator. It further correlated with dose-dependent mitochondrial reactive oxygen species production and cytotoxicity, indicating that inflammasome activation resulted from mitochondrial damage. However, both NLRP3 depletion and inhibition of K+ efflux mitigated abacavir-induced mitochondrial reactive oxygen species production and cytotoxicity, suggesting that these processes were secondary to NLRP3 activation. Instead, depletion of cardiolipin synthase 1 abolished abacavir-induced IL-1ß secretion, suggesting that mitochondrial cardiolipin release may trigger abacavir-induced inflammasome activation. Our data identify abacavir as a novel inflammasome-stimulating drug allergen. They implicate a potential contribution of innate immune activation to medication-induced delayed-type hypersensitivity, which may stimulate new concepts for treatment and prevention of drug allergies.


Subject(s)
Dideoxynucleosides/pharmacology , Inflammasomes/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Reverse Transcriptase Inhibitors/pharmacology , Caspase 1/metabolism , Cells, Cultured , Gene Knockdown Techniques , Humans , Immunity, Innate , Inflammasomes/immunology , Inflammasomes/metabolism , Interleukin-1beta/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Potassium/metabolism , Reactive Oxygen Species/metabolism
3.
J Neuroimmunol ; 168(1-2): 175-82, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16126281

ABSTRACT

Subcutaneous Interferon-beta (IFN-beta) injections for the treatment of multiple sclerosis (MS) frequently cause inflammatory injection site reactions. To study the role of chemokines we obtained skin biopsies from 7 MS patients 24 h after injection. At the IFN-beta but not at the contralateral placebo injection sites, we observed strong IP-10/CXCL10 and moderate MCP-1/CCL2 expression associated with extensive perivascular, highly CXCR3-positive T cell and macrophage infiltrates. Primary human skin cells displayed a comparable pattern of chemokine induction after stimulation with IFN-beta in vitro. IFN-beta may therefore trigger inflammatory skin reactions through local chemokine induction followed by rapid immune cell extravasation.


Subject(s)
Gene Expression Regulation/drug effects , Interferon-beta/therapeutic use , Multiple Sclerosis/drug therapy , Skin/drug effects , Antigens, CD/metabolism , Biopsy , Cells, Cultured , Chemokines/genetics , Chemokines/metabolism , Cytokines/genetics , Cytokines/metabolism , Cytokines/pharmacology , Dose-Response Relationship, Drug , Electrophoretic Mobility Shift Assay/methods , Enzyme-Linked Immunosorbent Assay/methods , Female , Gene Expression Regulation/physiology , Humans , Immunohistochemistry/methods , In Situ Hybridization/methods , Injections, Subcutaneous/methods , Male , Multiple Sclerosis/pathology , Multiple Sclerosis/physiopathology , Skin/pathology
5.
Arch Ophthalmol ; 121(6): 825-31, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12796254

ABSTRACT

OBJECTIVE: To investigate in vivo expression of chemokines in normal and inflamed human corneas, to determine whether chemokines are responsible for the recruitment of inflammatory cells. METHODS: In situ hybridization of the CXC chemokines growth-related oncogene-alpha (Gro-alpha) (CXCL-1), interleukin 8 (CXCL-8), macrophage interferon-gamma inducible gene (CXCL-9), and interferon-gamma inducible protein 10 (CXCL-10) and of the CC chemokines macrophage chemoattractant protein 1 (MCP-1) (CCL-2), macrophage inflammatory protein 1alpha (CCL-3), and regulated on activation, normal T-cell expressed and secreted (CCL-5) was performed to localize chemokine messenger RNA. Immunohistochemistry was used to identify the cellular infiltrate within the cornea. Three normal human eyes were compared with eyes enucleated because of chronic inflammation (n = 10), secondary to perforating injuries. RESULTS: In normal corneas, no chemokine expression was detected. In inflamed lesions, a high intensity of signals from Gro-alpha (CXCL-1) and MCP-1 (CCL-2) messenger RNA was observed in limbal epithelium and from Gro-alpha (CXCL-1), interleukin 8 (CXCL-8), and MCP-1 (CCL-2) in corneal stroma. The Gro-alpha (CXCL-1) was the only chemokine expressed by central corneal epithelium. All other examined chemokines were only moderately expressed in limbus and corneal stroma, or barely detectable. CONCLUSIONS: These cytokines are important agents in the cytokine network and contribute to the cell-specific and spatially restricted recruitment of neutrophils and mononuclear cells in acute inflammatory lesions of the human cornea. Clinical Relevance Understanding the role of chemokines in corneal inflammation may lead to the development of a selective receptor blockage of highly expressed chemokines to inhibit the recruitment of leukocyte subsets.


Subject(s)
Chemokine CCL2/genetics , Chemokines/genetics , Chemotactic Factors/genetics , Intercellular Signaling Peptides and Proteins/genetics , Interleukin-8/genetics , Keratitis/metabolism , Antibodies, Monoclonal , Chemokine CCL2/metabolism , Chemokine CCL4 , Chemokine CXCL1 , Chemokine CXCL10 , Chemokine CXCL9 , Chemokines/metabolism , Chemokines, CXC/genetics , Chemokines, CXC/metabolism , Chemotactic Factors/metabolism , Cornea/metabolism , Eye Injuries, Penetrating/complications , Eye Injuries, Penetrating/metabolism , Humans , Immunoenzyme Techniques , In Situ Hybridization , Inflammation , Intercellular Signaling Peptides and Proteins/metabolism , Interleukin-8/metabolism , Keratitis/etiology , Langerhans Cells/physiology , Macrophage Inflammatory Proteins/genetics , Macrophage Inflammatory Proteins/metabolism , Macrophages/physiology , Neutrophils/physiology , RNA, Messenger/metabolism , T-Lymphocytes/physiology
6.
Nature ; 417(6891): 861-6, 2002 Jun 20.
Article in English | MEDLINE | ID: mdl-12075355

ABSTRACT

The I kappa B kinase (IKK), consisting of the IKK1 and IKK2 catalytic subunits and the NEMO (also known as IKK gamma) regulatory subunit, phosphorylates I kappa B proteins, targeting them for degradation and thus inducing activation of NF-kappa B (reviewed in refs 1, 2). IKK2 and NEMO are necessary for NF-kappa B activation through pro-inflammatory signals. IKK1 seems to be dispensable for this function but controls epidermal differentiation independently of NF-kappa B. Previous studies suggested that NF-kappa B has a function in the growth regulation of epidermal keratinocytes. Mice lacking RelB or I kappa B alpha, as well as both mice and humans with heterozygous NEMO mutations, develop skin lesions. However, the function of NF-kappa B in the epidermis remains unclear. Here we used Cre/loxP-mediated gene targeting to investigate the function of IKK2 specifically in epidermal keratinocytes. IKK2 deficiency inhibits NF-kappa B activation, but does not lead to cell-autonomous hyperproliferation or impaired differentiation of keratinocytes. Mice with epidermis-specific deletion of IKK2 develop a severe inflammatory skin disease, which is caused by a tumour necrosis factor-mediated, alpha beta T-cell-independent inflammatory response that develops in the skin shortly after birth. Our results suggest that the critical function of IKK2-mediated NF-kappa B activity in epidermal keratinocytes is to regulate mechanisms that maintain the immune homeostasis of the skin.


Subject(s)
Epidermis/drug effects , Epidermis/enzymology , Gene Deletion , Protein Serine-Threonine Kinases/deficiency , Skin Diseases/chemically induced , Skin Diseases/pathology , Tumor Necrosis Factor-alpha/pharmacology , Animals , Apoptosis , Cell Differentiation , Cell Division , Epidermis/metabolism , Epidermis/pathology , I-kappa B Kinase , In Situ Hybridization , In Situ Nick-End Labeling , Inflammation/chemically induced , Inflammation/enzymology , Inflammation/genetics , Inflammation/pathology , Keratinocytes/drug effects , Keratinocytes/enzymology , Keratinocytes/metabolism , Keratinocytes/pathology , Mice , Mice, Knockout , NF-kappa B/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Skin Diseases/enzymology , Skin Diseases/genetics
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