Innate and Adaptive Immune Mechanisms in Arthritis

Summary

Principal Investigator: RICHARD J BUCALA
Abstract: ABSTRACT Rheumatoid arthritis results from a dysregulation in host immunity. Since our initial cloning of murine macrophage migration inhibitory factor (MIF), we have focused on the role of this mediator in the pathogenesis of rheumatoid arthritis. We showed that anti-MIF is protective in experimental arthritis and we reported on MIF's ability to override glucocorticoid immunosuppression, induce sustained activation of ERK1/2 MAP kinases, and promote inflammation by inhibiting activation-induced apoptosis. The importance of MIF in human disease was validated by our discovery of high-expression MIF alleles and their association with rheumatoid arthritis severity;these data were confirmed recently in a larger multi- center study and extended to juvenile idiopathic arthritis. In the currently funded period, we elucidated MIF function by creating genetic models for the complete and cell-lineage specific deletion of MIF (MIF-KO, mif flox), and we developed a "knock-in" mouse encoding a mutant MIF that resolved questions about the protein's enigmatic tautomerase activity. We also established that MIF signal transduction requires a complex of two proteins: CD74, which binds MIF, and CD44, which initiates signaling by activating Src family tyrosine kinases. In this competitive renewal, we will focus on the function of the recently elucidated MIF receptor. Our Specific Aims are: 1. Define the Role of the MIF Receptor Complex (CD74/CD44) in the Adaptive Immune Response. Our working hypothesis is that signaling through the MIF receptor sustains the survival of activated T lymphocytes and regulates the adaptive immune response. 2. Define the Functional Importance of the MIF Signaling Receptor, CD44, and of CD44 Variant Isoforms in the Immunopathology of Rheumatoid Arthritis. The expression of CD44 splice variants in T cells is associated with an enhanced trafficking response;and in stromal cells, with an increase in invasive phenotype. Our working hypothesis is that MIF induces the alternative splicing of CD44, which regulates MIF-dependent responses and contributes to the immunopathogenesis of rheumatoid arthritis. 3. Identify High-potency, Small Molecule Antagonists of the MIF Binding Receptor (CD74). Structure-function studies indicate that MIF's N-terminal region binds to the CD74 component of the MIF receptor. We will evaluate small molecules that were rationally designed to bind to the MIF N-terminal region for their ability to inhibit MIF interaction with CD74 and ameliorate experimentally-induced arthritis. The information to be gained will have broad application because it will provide mechanistic insight into how the MIF receptor complex (CD74/CD44) contributes to the immunopathology of rheumatoid arthritis. The translational impact of these studies is that a more precise definition of MIF-receptor action will accelerate the development of small molecule MIF inhibitors. Such inhibitors may show greatest efficacy in those patients with high-expression MIF alleles and who manifest an MIF-dependent form of inflammatory disease.
Funding Period: 2004-01-23 - 2014-08-31
more information: NIH RePORT

Top Publications

  1. pmc HLA-DRα1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis
    Roberto Meza-Romero
    Neuroimmunology Research, Department of Veterans Affairs Medical Center, Portland, OR 97239
    J Immunol 192:4164-73. 2014
  2. pmc D-dopachrome tautomerase (D-DT or MIF-2): doubling the MIF cytokine family
    Melanie Merk
    Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, LMU Munich, Germany
    Cytokine 59:10-7. 2012
  3. pmc The cytokine midkine and its receptor RPTPζ regulate B cell survival in a pathway induced by CD74
    Sivan Cohen
    Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
    J Immunol 188:259-69. 2012
  4. pmc Dual effect of the macrophage migration inhibitory factor gene on the development and severity of human systemic lupus erythematosus
    Antoine Sreih
    Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Arthritis Rheum 63:3942-51. 2011
  5. pmc The latency-associated nuclear antigen, a multifunctional protein central to Kaposi's sarcoma-associated herpesvirus latency
    Mary E Ballestas
    Department of Pediatrics, Division of Infectious Diseases, University of Alabama in Birmingham, School of Medicine, Children s Harbor Building, Room 148, 1600 6th Ave South, Birmingham, AL 35233, USA
    Future Microbiol 6:1399-413. 2011
  6. pmc Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74
    Daniel Heinrichs
    Medical Department III, Rheinisch Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany
    Proc Natl Acad Sci U S A 108:17444-9. 2011
  7. pmc Drug repositioning and pharmacophore identification in the discovery of hookworm MIF inhibitors
    Yoonsang Cho
    Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
    Chem Biol 18:1089-101. 2011
  8. pmc The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF)
    Melanie Merk
    Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
    Proc Natl Acad Sci U S A 108:E577-85. 2011
  9. pmc Benzisothiazolones as modulators of macrophage migration inhibitory factor
    William L Jorgensen
    Department of Chemistry, Yale University, New Haven, CT 06520 8107, USA
    Bioorg Med Chem Lett 21:4545-9. 2011
  10. pmc Role of macrophage migration inhibitory factor in the Th2 immune response to epicutaneous sensitization
    Rituparna Das
    Department of Medicine, Yale University School of Medicine, The Anlyan Center Room S525, New Haven, CT 06520 8031, USA
    J Clin Immunol 31:666-80. 2011

Detail Information

Publications57

  1. pmc HLA-DRα1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitis
    Roberto Meza-Romero
    Neuroimmunology Research, Department of Veterans Affairs Medical Center, Portland, OR 97239
    J Immunol 192:4164-73. 2014
    ....
  2. pmc D-dopachrome tautomerase (D-DT or MIF-2): doubling the MIF cytokine family
    Melanie Merk
    Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, LMU Munich, Germany
    Cytokine 59:10-7. 2012
    ..In this review, we highlight the similarities and differences between MIF and D-DT, which we propose to designate "MIF-2", and discuss the implication of D-DT/MIF-2 expression for MIF-based therapies...
  3. pmc The cytokine midkine and its receptor RPTPζ regulate B cell survival in a pathway induced by CD74
    Sivan Cohen
    Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
    J Immunol 188:259-69. 2012
    ..These findings could pave the way toward understanding the mechanisms shaping B cell survival and suggest novel therapeutic strategies based on the blockade of the MK/RPTPζ-dependent survival pathway...
  4. pmc Dual effect of the macrophage migration inhibitory factor gene on the development and severity of human systemic lupus erythematosus
    Antoine Sreih
    Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Arthritis Rheum 63:3942-51. 2011
    ..To study the effect of the innate cytokine macrophage migration inhibitory factor (MIF) on the susceptibility and severity of systemic lupus erythematosus (SLE) in a multinational population of 1,369 Caucasian and African American patients...
  5. pmc The latency-associated nuclear antigen, a multifunctional protein central to Kaposi's sarcoma-associated herpesvirus latency
    Mary E Ballestas
    Department of Pediatrics, Division of Infectious Diseases, University of Alabama in Birmingham, School of Medicine, Children s Harbor Building, Room 148, 1600 6th Ave South, Birmingham, AL 35233, USA
    Future Microbiol 6:1399-413. 2011
    ..In addition to episome maintenance, LANA has transcriptional regulatory effects and affects cell growth. LANA exerts these functions through interactions with different cell proteins...
  6. pmc Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74
    Daniel Heinrichs
    Medical Department III, Rheinisch Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany
    Proc Natl Acad Sci U S A 108:17444-9. 2011
    ..In conclusion, we describe a previously unexplored antifibrotic function of MIF that is mediated by the CD74/AMPK signaling pathway in HSCs. The results imply MIF and CD74 as targets for treatment of liver diseases...
  7. pmc Drug repositioning and pharmacophore identification in the discovery of hookworm MIF inhibitors
    Yoonsang Cho
    Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
    Chem Biol 18:1089-101. 2011
    ..Structure-activity relationships of a pharmacophore based on furosemide included one analog that binds similarly to the active site, yet does not inhibit the Na-K-Cl symporter (NKCC1) responsible for diuretic activity...
  8. pmc The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF)
    Melanie Merk
    Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
    Proc Natl Acad Sci U S A 108:E577-85. 2011
    ..These data indicate that D-DT is a MIF-like cytokine with an overlapping spectrum of activities that are important for our understanding of MIF-dependent physiology and pathology...
  9. pmc Benzisothiazolones as modulators of macrophage migration inhibitory factor
    William L Jorgensen
    Department of Chemistry, Yale University, New Haven, CT 06520 8107, USA
    Bioorg Med Chem Lett 21:4545-9. 2011
    ..Consistently, both compounds were also found to retard the MIF-dependent phosphorylation of ERK1/2 in human synovial fibroblasts...
  10. pmc Role of macrophage migration inhibitory factor in the Th2 immune response to epicutaneous sensitization
    Rituparna Das
    Department of Medicine, Yale University School of Medicine, The Anlyan Center Room S525, New Haven, CT 06520 8031, USA
    J Clin Immunol 31:666-80. 2011
    ..This defect is most profound when both T cells and antigen-presenting cells are lacking MIF. These data suggest that MIF is crucial both for the sensitization and the elicitation phases of a Th2-type immune response in allergic disease...
  11. pmc Macrophage migration inhibitory factor regulates neutrophil chemotactic responses in inflammatory arthritis in mice
    Leilani L Santos
    Monash Medical Centre, Clayton, Victoria, Australia
    Arthritis Rheum 63:960-70. 2011
    ..The effects of MIF on neutrophil recruitment are unknown. This study was undertaken to investigate the contribution of MIF to the regulation of neutrophil chemotactic responses...
  12. pmc Macrophage migration inhibitory factor and CD74 regulate macrophage chemotactic responses via MAPK and Rho GTPase
    Huapeng Fan
    Department of Medicine, Centre for Inflammatory Diseases, Monash University, Monash Medical Centre, Clayton, Victoria 3168, Australia
    J Immunol 186:4915-24. 2011
    ..These data demonstrate that MIF and CD74 play previously unappreciated roles in CCL2-induced macrophage adhesion and migration, and they indicate that MIF and CD74 mediate this effect via both common and independent mechanisms...
  13. pmc A novel allosteric inhibitor of macrophage migration inhibitory factor (MIF)
    Fengwei Bai
    L2 Diagnostics, LLC, New Haven, CT 06511, USA
    J Biol Chem 287:30653-63. 2012
    ..The mode of p425 binding reveals a unique way to block the activity of the cytokine for potential therapeutic benefit in MIF-associated diseases...
  14. ncbi Flow cytometric identification of fibrocytes in scleroderma lung disease
    Thomas M Russell
    Section of Pulmonary and Critical Care Medicine, Department of Medicine, Yale University, New Haven, CT, USA
    Methods Mol Biol 900:327-46. 2012
    ..It is hoped that this information will allow further investigation of the role that fibrocytes might play in Scleroderma-related lung disease and perhaps lead to new areas of study in this difficult-to-treat and deadly disease...
  15. pmc Macrophage migration inhibitory factor: association of -794 CATT5-8 and -173 G>C polymorphisms with TNF-α in systemic lupus erythematosus
    U De la Cruz-Mosso
    Instituto de Investigación en Ciencias Biomédicas Programa de Doctorado en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
    Hum Immunol 75:433-9. 2014
    ..In conclusion, MIF gene polymorphisms are associated with SLE susceptibility and with an increase of TNF-α serum levels in a Mexican-Mestizo population. ..
  16. pmc The role of macrophage migration inhibitory factor in autoimmune liver disease
    David N Assis
    Department of Medicine, Yale University School of Medicine, New Haven, CT
    Hepatology 59:580-91. 2014
    ..Significantly higher levels of CD74 were found in patients with PBC versus AIH and controls...
  17. pmc Macrophage migration inhibitory factor receptor CD74 mediates alphavirus-induced arthritis and myositis in murine models of alphavirus infection
    Lara J Herrero
    Griffith University, Gold Coast Campus, Southport, Queensland, Australia
    Arthritis Rheum 65:2724-36. 2013
    ..The present study was undertaken to characterize the role of CD74, a cell surface receptor of MIF, in both RRV- and CHIKV-induced alphavirus arthritides...
  18. pmc MIF intersubunit disulfide mutant antagonist supports activation of CD74 by endogenous MIF trimer at physiologic concentrations
    Chengpeng Fan
    Department of Pharmacology, Yale University, New Haven, CT 06510, USA
    Proc Natl Acad Sci U S A 110:10994-9. 2013
    ..This conclusion has implications for therapeutic development. ..
  19. pmc Partial MHC class II constructs inhibit MIF/CD74 binding and downstream effects
    Gil Benedek
    Department of Veterans Affairs Medical Center, Neuroimmunology Research, Portland, OR 97239, USA
    Eur J Immunol 43:1309-21. 2013
    ..Thus, binding of partial MHC complexes to CD74 blocks both the accessibility and availability of CD74 for MIF binding and downstream inflammatory activity...
  20. pmc Macrophage-derived, macrophage migration inhibitory factor (MIF) is necessary to induce disease in the K/BxN serum-induced model of arthritis
    Anjana Singh
    Department of Natural Sciences, Immunology and Cell Biology, University of Applied Sciences, von Liebig Str 20, 53359 Rheinbach, Germany
    Rheumatol Int 33:2301-8. 2013
    ....
  21. pmc Small molecular modulation of macrophage migration inhibitory factor in the hyperoxia-induced mouse model of bronchopulmonary dysplasia
    Huanxing Sun
    Department of Pediatrics, Yale University, New Haven, CT 06520, USA
    Respir Res 14:27. 2013
    ..The role and mechanism of action of MIF in bronchopulmonary dysplasia (BPD) are not known. We hypothesized that increased MIF signaling would ameliorate the pulmonary phenotype of BPD in the mouse lung...
  22. pmc CD84 is a survival receptor for CLL cells
    I Binsky-Ehrenreich
    Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
    Oncogene 33:1006-16. 2014
    ..These findings suggest novel therapeutic strategies based on the blockade of this CD84-dependent survival pathway. ..
  23. pmc Macrophage migration inhibitory factor (MIF): genetic evidence for participation in early onset and early stage rheumatoid arthritis
    M A Llamas-Covarrubias
    Functional Immunogenetics Group and PhD Program in Biomedical Sciences, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
    Cytokine 61:759-65. 2013
    ..In conclusion, the MIF gene and protein are associated with RA in a western Mexican population, with a main contribution onto early onset and early stages of disease...
  24. pmc Role of macrophage migration inhibitory factor in the regulatory T cell response of tumor-bearing mice
    Susanna Choi
    Research Institute of Immunobiology, Catholic Research Institute of Medical Science, Seoul, Korea 137 040
    J Immunol 189:3905-13. 2012
    ..Taken together, our data suggest that MIF promotes tumor growth by increasing Treg generation through the modulation of IL-2 production. Thus, anti-MIF treatment might be useful in enhancing the adaptive immune response to colon cancers...
  25. pmc MIF, MIF alleles, and prospects for therapeutic intervention in autoimmunity
    Richard Bucala
    Department of Medicine, Section of Rheumatology, Yale University School of Medicine, The Anlyan Center for Biomedcal Research, S521, 300 Cedar Street, New Haven, CT 06520 8031, USA
    J Clin Immunol 33:S72-8. 2013
    ....
  26. pmc A small-molecule macrophage migration inhibitory factor antagonist protects against glomerulonephritis in lupus-prone NZB/NZW F1 and MRL/lpr mice
    Lin Leng
    Department of Medicine, Yale University, New Haven, CT 06520, USA
    J Immunol 186:527-38. 2011
    ..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...
  27. pmc Receptor agonists of macrophage migration inhibitory factor
    William L Jorgensen
    Department of Chemistry, Yale University, New Haven, CT 06520, USA
    Bioorg Med Chem Lett 20:7033-6. 2010
    ..The compounds contain a triazole core that is readily assembled via Cu-catalyzed click chemistry. The agonist and antagonist behaviors were confirmed via study of MIF-dependent ERK1/2 phosphorylation in human fibroblasts...
  28. pmc Human cytomegalovirus paralyzes macrophage motility through down-regulation of chemokine receptors, reorganization of the cytoskeleton, and release of macrophage migration inhibitory factor
    Giada Frascaroli
    Institute for Virology, University of Ulm, Ulm, Germany
    J Immunol 182:477-88. 2009
    ..Our findings reveal that HCMV uses different mechanisms to interfere with movement and positioning of macrophages, possibly leading to an impairment of antiviral responses and to an enhancement of the local inflammation...
  29. pmc Discovery of human macrophage migration inhibitory factor (MIF)-CD74 antagonists via virtual screening
    Zoe Cournia
    Department of Chemistry, Yale University, New Haven, Connecticut 06520 8107, USA
    J Med Chem 52:416-24. 2009
    ..Inhibition of MIF tautomerase activity was also established for many of the compounds with IC(50) values as low as 0.5 microM; Michaelis-Menten analysis was performed for two cases and confirmed the competitive inhibition...
  30. pmc Toll-like receptors in systemic lupus erythematosus; prospects for therapeutic intervention
    Wan Uk Kim
    Department of Internal Medicine, School of Medicine, Catholic University of Korea, Seoul, South Korea
    Autoimmun Rev 8:204-8. 2009
    ..Pharmacologic modulation of TLR-directed pathways may offer new therapeutic approaches for the treatment of SLE...
  31. pmc Macrophage migration inhibitory factor contributes to the immune escape of ovarian cancer by down-regulating NKG2D
    Mathias Krockenberger
    Department for Obstetrics and Gynecology, University of Wurzburg, Wurzburg, Germany
    J Immunol 180:7338-48. 2008
    ..Together with the additional tumorigenic properties of MIF, this finding provides a rationale for novel small-molecule inhibitors of MIF to be used for the treatment of MIF-secreting cancers...
  32. ncbi A role for macrophage migration inhibitory factor in the neonatal respiratory distress syndrome
    Katharine A Kevill
    Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA
    J Immunol 180:601-8. 2008
    ..03). This study demonstrates for the first time a role for MIF in lung maturation, and supports a protective role for MIF in newborn lung disease...
  33. ncbi Macrophage migration inhibitory factor induces B cell survival by activation of a CD74-CD44 receptor complex
    Yael Gore
    Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel
    J Biol Chem 283:2784-92. 2008
    ..Thus, MIF regulates the adaptive immune response by maintaining the mature B cell population...
  34. ncbi The proinflammatory cytokine macrophage migration inhibitory factor regulates glucose metabolism during systemic inflammation
    Toshiya Atsumi
    Graduate School of Medicine, Hokkaido University, Sapporo, Japan
    J Immunol 179:5399-406. 2007
    ..Genetic MIF deficiency also promotes adipogenesis, which is in accord with a downstream role for MIF in the action of TNF-alpha. These studies support an important role for MIF in host glucose metabolism during sepsis...
  35. ncbi Macrophage migration inhibitory factor (MIF) gene polymorphisms are associated with increased prostate cancer incidence
    K L Meyer-Siegler
    Research and Development 151, Bay Pines VA Healthcare System, Bay Pines, FL 33744, USA
    Genes Immun 8:646-52. 2007
    ..Individuals with -173G/C, -173C/C and -794 7-CATT MIF genotypes have an increased incidence of CaP and these genotypes may serve as an independent marker for cancer recurrence...
  36. pmc Null mutation for macrophage migration inhibitory factor (MIF) is associated with less aggressive bladder cancer in mice
    John A Taylor
    Division of Urology, University of Connecticut Health Center, Farmington, CT, USA
    BMC Cancer 7:135. 2007
    ..We studied the development of bladder cancer in wild type (WT) and MIF knockout (KO) mice given N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), a known carcinogen, to determine the role of MIF in bladder cancer initiation and progression...
  37. ncbi Macrophage migration inhibitory factor induces MMP-9 expression in macrophages via the MEK-ERK MAP kinase pathway
    Xiyong Yu
    The Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People s Hospital, Guangzhou 510080, China
    J Interferon Cytokine Res 27:103-9. 2007
    ..MIF activates the MEK-ERK MAP kinase pathway to induce MMP-9 expression by murine macrophages. Activation of this pathway is necessary for MMP-9 expression and activation in response to MIF stimulation...
  38. ncbi Macrophage migration inhibitory factor promoter polymorphisms and the clinical expression of scleroderma
    Sou Pan Wu
    Yale University School of Medicine, New Haven, Connecticut 06520 8031, USA
    Arthritis Rheum 54:3661-9. 2006
    ..To investigate the potential association between functional polymorphisms in the gene for the innate mediator, macrophage migration inhibitory factor (MIF), and the clinical expression of systemic sclerosis (SSc)...
  39. pmc CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex
    Xuerong Shi
    Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    Immunity 25:595-606. 2006
    ..These data establish CD44 as an integral member of the CD74 receptor complex leading to MIF signal transduction...
  40. pmc A tautomerase-null macrophage migration-inhibitory factor (MIF) gene knock-in mouse model reveals that protein interactions and not enzymatic activity mediate MIF-dependent growth regulation
    Gunter Fingerle-Rowson
    Clinic I for Internal Medicine, Hematology and Oncology, University Hospital Cologne, Cologne, Germany
    Mol Cell Biol 29:1922-32. 2009
    ..These data provide genetic evidence that MIF's intrinsic tautomerase activity is dispensable for this cytokine's growth-regulatory properties and support a role for the N-terminal region in protein-protein interactions...
  41. pmc MIF deficiency reduces chronic inflammation in white adipose tissue and impairs the development of insulin resistance, glucose intolerance, and associated atherosclerotic disease
    Lars Verschuren
    TNO Quality of Life, Biosciences, Leiden, The Netherlands
    Circ Res 105:99-107. 2009
    ....
  42. pmc Activation of the JNK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on CXCR4 and CD74
    Hongqi Lue
    Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Pauwelsstrasse 30, Aachen, Germany
    Cell Signal 23:135-44. 2011
    ..Together, these data show that the CXCR4/CD74/SRC/PI3K axis mediates a rapid and transient activation of the JNK pathway as triggered by the inflammatory cytokine MIF in T cells and fibroblasts...
  43. pmc A role for the B-cell CD74/macrophage migration inhibitory factor pathway in the immunomodulation of systemic lupus erythematosus by a therapeutic tolerogenic peptide
    Smadar Lapter
    Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
    Immunology 132:87-95. 2011
    ..Treatment with hCDR1 diminished the expression of those molecules to the levels determined for young healthy mice. These results suggest that the CD74/MIF pathway plays an important role in lupus pathology...
  44. pmc Optimization of N-benzyl-benzoxazol-2-ones as receptor antagonists of macrophage migration inhibitory factor (MIF)
    Alissa A Hare
    Department of Chemistry, Yale University, New Haven, CT 06520 8107, USA
    Bioorg Med Chem Lett 20:5811-4. 2010
    ..Additional studies for one of the potent inhibitors demonstrated that it is not a covalent inhibitor of MIF and that it attenuates MIF-dependent ERK1/2 phosphorylation in human synovial fibroblasts...
  45. pmc c-Met and its ligand hepatocyte growth factor/scatter factor regulate mature B cell survival in a pathway induced by CD74
    Maya Gordin
    Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
    J Immunol 185:2020-31. 2010
    ..Thus, the CD74-HGF/c-Met axis defines a novel physiologic survival pathway in mature B cells, resulting in the control of the humoral immune response...
  46. pmc Increased TLR4 expression and downstream cytokine production in immunosuppressed adults compared to non-immunosuppressed adults
    Dana W Dunne
    Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
    PLoS ONE 5:e11343. 2010
    ..We studied monocyte Toll-like receptor (TLR) expression and cytokine production in 137 patients with autoimmune diseases who were maintained on immunosuppressive medications and 419 non-immunosuppressed individuals...
  47. pmc Macrophage migration inhibitory factor (MIF): a promising biomarker
    Gerrit Grieb
    Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
    Drug News Perspect 23:257-64. 2010
    ..In this article, we review the clinical data of MIF and discuss its potential as a biomarker for different disease applications...
  48. pmc Polymorphisms in the macrophage migration inhibitory factor gene and bone loss in postmenopausal women
    Maria Swanberg
    Clinical and Molecular Osteoporosis Research Unit, Lund University, Department of Clinical Sciences, Malmo University Hospital, Entrance 21, Floor 4, UMAS, SE 20502 Malmo, Sweden
    Bone 47:424-9. 2010
    ..We conclude that MIF promoter polymorphisms have modest effects on bone remodeling and are associated with the rate of bone loss in elderly women...
  49. pmc TAp63 regulates VLA-4 expression and chronic lymphocytic leukemia cell migration to the bone marrow in a CD74-dependent manner
    Inbal Binsky
    Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
    J Immunol 184:4761-9. 2010
    ..These results could form the basis of novel therapeutic strategies aimed at blocking homing of CLL cells in their return to the BM and attenuating their survival...
  50. pmc A new class of isothiocyanate-based irreversible inhibitors of macrophage migration inhibitory factor
    Hajer Ouertatani-Sakouhi
    Laboratory of Molecular Neurobiology and Functional Neuroproteomics, Brain Mind Institute and Institute of Biotechnology and Bioengineering, Ecole Polytechnique Federale de Lausanne EPFL, CH 1015 Lausanne, Switzerland
    Biochemistry 48:9858-70. 2009
    ..Together, these findings highlight the role of tertiary structure in modulating the biochemical and biological activities of MIF and present new opportunities for modulating MIF biological activities in vivo...
  51. pmc A functional heteromeric MIF receptor formed by CD74 and CXCR4
    Verena Schwartz
    Department of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen, Germany
    FEBS Lett 583:2749-57. 2009
    ..Thus, CD74 forms functional complexes with CXCR4 that mediate MIF-specific signaling...
  52. pmc Glucocorticoid-induced MIF expression by human CEM T cells
    Lin Leng
    Yale University School of Medicine, New Haven, CT 06520, USA
    Cytokine 48:177-85. 2009
    ..These data support a glucocorticoid-mediated MIF secretion response by T cells that may contribute to the regulation of the adaptive immune response...
  53. ncbi Insight into the biology of macrophage migration inhibitory factor (MIF) revealed by the cloning of its cell surface receptor
    Lin Leng
    Department of Medicine, Yale University School of Medicine, The Anlyan Center, S525, 300 Cedar Street, New Haven CT 06520 8056, USA
    Cell Res 16:162-8. 2006
    ..The MIF receptor, like MIF, does not fall into any established family of protein mediators, providing both new challenges and opportunities for the structural and functional analysis of MIF signal transduction...

Research Grants31

  1. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
    ..We also want to understand why the immune system destroys hypocretin neurons in narcolepsy and to prevent/cure it. ..
  2. INNATE IMMUNE RESPONSE TO MICROBIAL INFECTION
    William M Nauseef; Fiscal Year: 2013
    ....
  3. G protein-coupled receptor kinase 3 regulation of leukocyte function in inflammat
    TERESA KATHLEEN TARRANT; Fiscal Year: 2013
    ....
  4. MIF AND THE HOST RESPONSE TO INFECTION
    RICHARD J BUCALA; Fiscal Year: 2013
    ..This work also will enable the identification of individuals who are at risk for severe infection and lethal outcome, so that appropriate measures can be taken to better treat their infections. ..
  5. Role of CX3CR1 in adaptive immunity during autoimmune encephalomyelitis
    Astrid E Cardona; Fiscal Year: 2013
    ..We will use knock-in mice expressing the human variant as a low affinity model to investigate the role of the I249/M280 in APC activation and T cell polarization in vivo during CNS autoimmunity. ..
  6. Therapeutic Application of Small Molecule MIF Inhibitors in Rheumatoid Arthritis
    Yoonsang Cho; Fiscal Year: 2013
    ..Outcomes of this proposed research will allow us to better understand MIF action to its receptors and also will provide potential drug leads for the treatment of inflammatory diseases. ..
  7. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  8. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  9. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  10. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  11. Therapeutic Opportunities for Pediatric Astrocytoma
    Rosalind A Segal; Fiscal Year: 2013
    ..The three projects interact with one another and are further unified by economies of scale enabled by an Innovative Neuropathology (INP) core. ..
  12. Autoimmunity Center of Excellence (ACE) at Stanford
    CHARLES GARRISON FATHMAN; Fiscal Year: 2013
    ..The Stanford ACE proposes clinical research projects that encompass three different autoimmune diseases (SSc, psoriatic arthritis and SJIA), and proposes to study the MoA of therapeutics for preventing or treating different Al diseases. ..
  13. Developing Small MIF Inhibitors for Rheumatoid Arthritis
    Christian Grant; Fiscal Year: 2013
    ..Dose finding studies and PK profiling will first be performed with a preference for oral dosing. An optimized dose and route of administration will then be chosen to test the therapeutic efficacy of two lead compounds in the RA models ..
  14. Blood Stem Cell Transplantation as Immunotherapy
    Samuel Strober; Fiscal Year: 2013
    ..The results are also expected to reduce the risk of graft versus host disease in patients given hematopoietic cell transplants to treat leukemia and lymphoma. (End of Abstract) ..
  15. CSHL CANCER CENTER SUPPORT GRANT
    BRUCE W STILLMAN; Fiscal Year: 2013
    ....