A Small-Molecule Macrophage Migration Inhibitory Factor Antagonist Protects against Glomerulonephritis in Lupus-Prone NZB/NZW F1 and MRL/lpr Mice
| العنوان: | A Small-Molecule Macrophage Migration Inhibitory Factor Antagonist Protects against Glomerulonephritis in Lupus-Prone NZB/NZW F1 and MRL/lpr Mice |
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| المؤلفون: | Lin Leng, David J. Nikolic-Paterson, Hui Y. Lan, Alvaro Arjona, Richard Bucala, Juan Fan, Michael Kashgarian, Zhinan Yin, Xiao R. Huang, Xin Du, Liang Chen, Dorothee Greven, David J. Austin, Elias Lolis |
| المصدر: | The Journal of Immunology. 186:527-538 |
| بيانات النشر: | The American Association of Immunologists, 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Mice, Inbred MRL lpr, Chemokine, animal diseases, Molecular Sequence Data, Immunology, chemical and pharmacologic phenomena, urologic and male genital diseases, medicine.disease_cause, CXCR4, Autoimmunity, Proinflammatory cytokine, Mice, Random Allocation, Chemokine receptor, Glomerulonephritis, otorhinolaryngologic diseases, medicine, Animals, Humans, Lupus Erythematosus, Systemic, Immunology and Allergy, Genetic Predisposition to Disease, Amino Acid Sequence, Receptors, Immunologic, Macrophage Migration-Inhibitory Factors, Mice, Knockout, Lupus erythematosus, Systemic lupus erythematosus, Mice, Inbred NZB, biology, Gene Expression Profiling, Isoxazoles, medicine.disease, female genital diseases and pregnancy complications, Intramolecular Oxidoreductases, Cell Migration Inhibition, biology.protein, Female, Macrophage migration inhibitory factor |
| الوصف: | Autoimmunity leads to the activation of innate effector pathways, proinflammatory cytokine production, and end-organ injury. Macrophage migration inhibitory factor (MIF) is an upstream activator of the innate response that mediates the recruitment and retention of monocytes via CD74 and associated chemokine receptors, and it has a role in the maintenance of B lymphocytes. High-expression MIF alleles also are associated with end-organ damage in different autoimmune diseases. We assessed the therapeutic efficacy of (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), an orally bioavailable MIF antagonist, in two distinct models of systemic lupus erythematosus: the NZB/NZW F1 and the MRL/lpr mouse strains. ISO-1, like anti-MIF, inhibited the interaction between MIF and its receptor, CD74, and in each model of disease, it reduced functional and histological indices of glomerulonephritis, CD74+ and CXCR4+ leukocyte recruitment, and proinflammatory cytokine and chemokine expression. Neither autoantibody production nor T and B cell activation were significantly affected, pointing to the specificity of MIF antagonism in reducing excessive proinflammatory responses. These data highlight the feasibility of targeting the MIF–MIF receptor interaction by small-molecule antagonism and support the therapeutic value of downregulating MIF-dependent pathways of tissue damage in systemic lupus erythematosus. |
| تدمد: | 1550-6606 0022-1767 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cd8c936b82f2119e2785e2cf32f7ec17Test https://doi.org/10.4049/jimmunol.1001767Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....cd8c936b82f2119e2785e2cf32f7ec17 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15506606 00221767 |
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