MIF AND THE HOST RESPONSE TO INFECTION

Summary

Principal Investigator: RICHARD J BUCALA
Abstract: DESCRIPTION (provided by applicant): Infectious pathogens can induce a fulminant innate response that contributes importantly to end- organ damage and to lethal sequelae such as septic shock. In 1993, we cloned murine macrophage migration inhibitory factor (MIF) as an upstream regulator of innate immunity and mediator of lethal shock. We defined MIF's ability to override glucocorticoid immunosuppression, induce sustained activation of the ERK1/2 MAP kinase, and inhibit activation-induced, monocyte/macrophage apoptosis. In the most recent funding period, we described a significant association between functional alleles in the human MIF gene (MIF) and clinical outcome from pneumonia. We also cloned the MIF receptor and identified signaling to require a complex of two transmembrane proteins: one mediating MIF-binding (CD74), and one initiating signal transduction (CD44). Our long-range goal remains to better define the role of MIF - now known to be encoded in a functionally polymorphic locus - on the pathogenesis and outcome of infection. Our overall hypothesis is that MIF plays a critical role in balancing the expression of a protective inflammatory response with one causing severe end-organ damage, and it is now supported both by experimental studies and by human genetic data. In this competitive renewal, we will follow-up on the genetic findings by pursuing the following three Specific Aims: 1. Define the Functional Impact of High- and Low-expression MIF Alleles on the Human Innate Immune Response. We will characterize the MIF-dependent responses of human monocytes and alveolar epithelial cells stimulated by TLR ligands that are representative of diverse microbial pathogens. Our working hypothesis is that human cells encoding high-expression MIF alleles will show a more activated phenotype and enhanced, downstream cytokine production when compared to cells encoding low-expression MIF alleles. 2. Establish the Utility of a Lung-specific, MIF Transgenic Mouse for the Study of Pulmonary Infection. We will study a transgenic mouse that overexpresses MIF in the lung. Such a mouse, when investigated in combination with MIF-KO mice, will enable mechanistic studies of MIF role's in the pathogenesis of different lung infections and provide an in vivo model of the responses of human subjects having high- or low-expression MIF alleles. 3. Define the Phenotype of a Tautomerase-null, MIF-Knockin Mouse in Models of Infection. We will use a genetic model to better define the structural basis for MIF action and address an unresolved question about the role of MIF's enigmatic tautomerization activity in its biologic function. We will study the responses to infection of a genetically-engineered "knockin" mouse that produces an MIF protein in which the catalytic proline that mediates tautomerase activity has been replaced by glycine (P1G-MIF). The information to be gained has important translation to human disease because it may allow for the identification of patients at risk for lethal outcome from different pathogens, whether bacteria, viruses, or emerging infectious agents. Better definition of MIF-dependent responses also will assist in the appropriate application of MIF-directed therapies, which are presently in pre-clinical development. PUBLIC HEALTH RELEVANCE: The innate response to infection has a critical role in determining whether the pathogen is eliminated or if the infected individual suffers lethal complications such as septic shock. The goal of this proposal is to understand how the cytokine, macrophage migration inhibitory factor (MIF), regulates the balance between protection from infection and severe inflammatory tissue damage. MIF is encoded in a functionally polymorphic genetic locus and recent work has shown an association between different MIF alleles and the clinical outcome from pneumonia. We hope to show how genetic variation in MIF influences the host response to particular infections, including bacterial pneumonia and influenza. If successful, this information will lead to the application of MIF-directed therapies for the treatment of particular infections and their complications. 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.
Funding Period: 1998-06-01 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. pmc Ostertagia ostertagi macrophage migration inhibitory factor is present in all developmental stages and may cross-regulate host functions through interaction with the host receptor
    Guanggang Qu
    Animal Parasitic Diseases Laboratory, Agricultural Research Service, USDA, Beltsville, MD 20705, USA Shangdong Binzhou Academy of Animal Science and Veterinary Medicine, Binzhou City, Shandong 256600, China
    Int J Parasitol 44:355-67. 2014
  2. ncbi Macrophage migration inhibitory factor enzymatic activity, lung inflammation, and cystic fibrosis
    Huzaifa Adamali
    School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
    Am J Respir Crit Care Med 186:162-9. 2012
  3. 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
  4. 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
  5. pmc Age-associated elevation in TLR5 leads to increased inflammatory responses in the elderly
    Feng Qian
    Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520 8031, USA
    Aging Cell 11:104-10. 2012
  6. 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
  7. ncbi Elevated levels of macrophage migration inhibitory factor in women with metabolic syndrome
    H R Kim
    Department of Anatomy and SNUMRC, Seoul National University College of Medicine, Seoul, Republic of Korea
    Horm Metab Res 43:642-5. 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 Lack of macrophage migration inhibitory factor in mice does not affect hallmarks of the inflammatory/immune response during the first week after stroke
    Ana R Inácio
    Laboratory for Experimental Brain Research, Department of Clinical Sciences, Lund University, BMC A13, 22184 Lund, Sweden
    J Neuroinflammation 8:75. 2011

Research Grants

Detail Information

Publications58

  1. pmc Ostertagia ostertagi macrophage migration inhibitory factor is present in all developmental stages and may cross-regulate host functions through interaction with the host receptor
    Guanggang Qu
    Animal Parasitic Diseases Laboratory, Agricultural Research Service, USDA, Beltsville, MD 20705, USA Shangdong Binzhou Academy of Animal Science and Veterinary Medicine, Binzhou City, Shandong 256600, China
    Int J Parasitol 44:355-67. 2014
    ..Given its dual role in self-regulation and molecular mimicry, this secreted parasite protein warrants investigation as a vaccine candidate against O. ostertagi infections in cattle...
  2. ncbi Macrophage migration inhibitory factor enzymatic activity, lung inflammation, and cystic fibrosis
    Huzaifa Adamali
    School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
    Am J Respir Crit Care Med 186:162-9. 2012
    ..We previously demonstrated that individual patients with cystic fibrosis (CF) who are genetically predisposed to be high MIF producers develop accelerated end-organ injury...
  3. 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...
  4. 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...
  5. pmc Age-associated elevation in TLR5 leads to increased inflammatory responses in the elderly
    Feng Qian
    Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520 8031, USA
    Aging Cell 11:104-10. 2012
    ..Elevated TLR5 may provide a critical mechanism to enhance immune responsiveness in older individuals...
  6. 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...
  7. ncbi Elevated levels of macrophage migration inhibitory factor in women with metabolic syndrome
    H R Kim
    Department of Anatomy and SNUMRC, Seoul National University College of Medicine, Seoul, Republic of Korea
    Horm Metab Res 43:642-5. 2011
    ..An elevation of systemic MIF in women with metabolic syndrome may contribute to pathogenesis of metabolic syndrome or to the development of metabolic syndrome-related diseases, such as atherosclerosis and type 2 diabetes mellitus...
  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 Lack of macrophage migration inhibitory factor in mice does not affect hallmarks of the inflammatory/immune response during the first week after stroke
    Ana R Inácio
    Laboratory for Experimental Brain Research, Department of Clinical Sciences, Lund University, BMC A13, 22184 Lund, Sweden
    J Neuroinflammation 8:75. 2011
    ..Since MIF regulates tissue inflammation, we studied the putative role of MIF in post-stroke inflammation...
  11. pmc Macrophage migration inhibitory factor: a downregulator of early T cell-dependent IFN-gamma responses in Plasmodium chabaudi adami (556 KA)-infected mice
    Diane Tshikudi Malu
    Departement des Sciences Biologiques, Universite du Quebec a Montreal, Québec H3B 3H5, Canada
    J Immunol 186:6271-9. 2011
    ..c. adami infection, MIF decreases IFN-γ secretion in CD4(+) T cells and, additionally, has the intrinsic ability to render CD4(+) T cells less capable of acquiring a robust Th1 phenotype when stimulated in the presence of IL-12...
  12. pmc Distinct clinical and immunologic profiles in severe malarial anemia and cerebral malaria in Zambia
    Philip E Thuma
    Malaria Institute at Macha, Choma, Zambia
    J Infect Dis 203:211-9. 2011
    ..The mechanisms of severe malarial anemia and cerebral malaria, which are extreme manifestations of Plasmodium falciparum malaria, are not fully understood...
  13. pmc Association of macrophage migration inhibitory factor (MIF) polymorphisms with risk of meningitis from Streptococcus pneumoniae
    Sarah Doernberg
    Department of Internal Medicine, Yale University School of Medicine, The Anlyan Center, S525, P O Box 208031, 300 Cedar Street, New Haven, CT 06520 8031, USA
    Cytokine 53:292-4. 2011
    ..We observed an association between a high-expression MIF allele and occurrence of pneumococcal meningitis...
  14. pmc A Plasmodium-encoded cytokine suppresses T-cell immunity during malaria
    Tiffany Sun
    Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
    Proc Natl Acad Sci U S A 109:E2117-26. 2012
    ..These findings indicate that Plasmodia actively interfere with the development of immunological memory and may account for the evolutionary conservation of parasite macrophage migration inhibitory factor orthologs...
  15. pmc Virtual screening and optimization yield low-nanomolar inhibitors of the tautomerase activity of Plasmodium falciparum macrophage migration inhibitory factor
    Markus K Dahlgren
    Department of Chemistry, Yale University, New Haven, Connecticut 06520 8107, USA
    J Med Chem 55:10148-59. 2012
    ..Thirty-one additional analogues were then designed, synthesized, and assayed. Three were found to be potent PfMIF tautomerase inhibitors with K(i) of ∼40 nM; they are also highly selective with K(i) > 100 μM for human MIF...
  16. pmc Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis
    Mark A Barnes
    Department of Molecular Medicine, Center for Liver Disease Research, Cleveland, OH, USA
    Hepatology 57:1980-91. 2013
    ..Chronic ethanol feeding also sensitized wildtype, but not MIF-/-, mice to lipopolysaccharide, increasing chemokine expression and monocyte recruitment into the liver...
  17. pmc Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium
    Marzena Schiwon
    Institute of Experimental Immunology, University Clinic of Bonn, 53127 Bonn, Germany
    Cell 156:456-68. 2014
    ..These findings identify helper macrophages and TNF as critical regulators in innate immunity against bacterial infections in epithelia. ..
  18. pmc Macrophage migration inhibitory factor deletion exacerbates pressure overload-induced cardiac hypertrophy through mitigating autophagy
    Xihui Xu
    Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, 1000 E University Ave, Laramie, WY 82071
    Hypertension 63:490-9. 2014
    ..These data indicate that endogenous MIF regulates the mammalian target of rapamycin signaling to activate autophagy to preserve cardiac geometry and protect against hypertrophic responses. ..
  19. pmc Macrophage migration inhibitory factor deficiency augments doxorubicin-induced cardiomyopathy
    Xihui Xu
    Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, School of Pharmacy, Laramie, WY
    J Am Heart Assoc 2:e000439. 2013
    ..This study was designed to evaluate the role of MIF in doxorubicin-induced cardiomyopathy and the underlying mechanism involved with a focus on autophagy...
  20. 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...
  21. pmc Macrophage migration inhibitory factor (MIF) is a critical mediator of the innate immune response to Mycobacterium tuberculosis
    Rituparna Das
    Department of Medicine, Yale School of Medicine, New Haven, CT 06510, USA
    Proc Natl Acad Sci U S A 110:E2997-3006. 2013
    ..Our data place MIF in a crucial upstream position in the innate immune response to mycobacteria and suggest that commonly occurring low expression MIF alleles confer an increased risk of TB disease in some populations. ..
  22. pmc Cytokines in sepsis: potent immunoregulators and potential therapeutic targets--an updated view
    Wibke Schulte
    Department of Internal Medicine, Yale University School of Medicine, The Anlyan Center, New Haven, CT 06520 8031, USA
    Mediators Inflamm 2013:165974. 2013
    ....
  23. pmc Characterization of Neospora caninum macrophage migration inhibitory factor
    Guanggang Qu
    Animal Parasitic Diseases Laboratory, Agricultural Research Service, USDA, Beltsville, MD 20705, USA Shangdong Binzhou Academy of Animal Science and Veterinary Medicine, Binzhou City, Shandong 256600, China
    Exp Parasitol 135:246-56. 2013
    ..This differential production of NcMIF by the pathologic and non-pathologic isolates of N. caninum may suggest a critical role of this molecule in the infectious pathogenesis of this parasite. ..
  24. pmc Limiting cardiac ischemic injury by pharmacological augmentation of macrophage migration inhibitory factor-AMP-activated protein kinase signal transduction
    Jingying Wang
    Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, NY 14214 3000, USA
    Circulation 128:225-36. 2013
    ..Small molecules that increase the affinity of MIF for its receptor have been recently designed, and we hypothesized that such agonists may enhance AMPK activation and limit ischemic tissue injury...
  25. pmc Macrophage migration inhibitory factor plays a permissive role in the maintenance of cardiac contractile function under starvation through regulation of autophagy
    Xihui Xu
    Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA
    Cardiovasc Res 99:412-21. 2013
    ..This study was designed to examine the role of MIF in cardiac homeostasis and autophagy regulation following an acute starvation challenge...
  26. pmc A critical regulatory role for macrophage migration inhibitory factor in hyperoxia-induced injury in the developing murine lung
    Huanxing Sun
    Department of Pediatrics, Yale University, New Haven, Connecticut, United States of America
    PLoS ONE 8:e60560. 2013
    ..The role and mechanism of action of MIF in hyperoxia-induced acute lung injury (HALI) in the newborn lung are not known. We hypothesized that MIF is a critical regulatory molecule in HALI in the developing lung...
  27. pmc Role of migratory inhibition factor in age-related susceptibility to radiation lung injury via NF-E2-related factor-2 and antioxidant regulation
    Biji Mathew
    Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL 60612 7227, USA
    Am J Respir Cell Mol Biol 49:269-78. 2013
    ..These findings implicate an important role for MIF in radiation-induced changes in lung-cell antioxidant concentrations via Nrf2, and suggest that MIF may contribute to age-related susceptibility to thoracic radiation. ..
  28. 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...
  29. pmc Macrophage migration inhibitory factor promotes cell death and aggravates neurologic deficits after experimental stroke
    Ana R Inácio
    Department of Clinical Sciences, Laboratory for Experimental Brain Research, Lund University, Lund, Sweden
    J Cereb Blood Flow Metab 31:1093-106. 2011
    ..We conclude that MIF promotes neuronal death and aggravates neurologic deficits after experimental stroke, which implicates MIF in the pathogenesis of neuronal injury after stroke...
  30. 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...
  31. pmc Orthologs of macrophage migration inhibitory factor from parasitic nematodes
    Jon J Vermeire
    Department of Pediatrics, Yale Child Health Research Center, Yale University School of Medicine, New Haven, CT 06520, USA
    Trends Parasitol 24:355-63. 2008
    ....
  32. pmc A Leishmania ortholog of macrophage migration inhibitory factor modulates host macrophage responses
    Daniela Kamir
    Yale University School of Medicine, New Haven, CT 06520, USA
    J Immunol 180:8250-61. 2008
    ..The ability of Lm1740MIF to inhibit apoptosis may facilitate the persistence of Leishmania within the macrophage and contribute to its evasion from immune destruction...
  33. pmc Acute lung injury induced by lipopolysaccharide is independent of complement activation
    Daniel Rittirsch
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
    J Immunol 180:7664-72. 2008
    ..Most strikingly, complement activation does not contribute to the development of ALI in the LPS model...
  34. 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...
  35. 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...
  36. ncbi Toll-like receptor modulation of murine cerebral malaria is dependent on the genetic background of the host
    Jason W Griffith
    Department of Internal Medicine, Yale University, 300 Cedar Street, New Haven, CT 06520, USA
    J Infect Dis 196:1553-64. 2007
    ..These results suggest that TLR signaling and host genetic background influences the pathogenesis of CM via modulation of cytokine production and T(reg) cell numbers...
  37. 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...
  38. pmc Abrogation of macrophage migration inhibitory factor decreases West Nile virus lethality by limiting viral neuroinvasion
    Alvaro Arjona
    Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
    J Clin Invest 117:3059-66. 2007
    ....
  39. pmc Structural and functional characterization of a secreted hookworm Macrophage Migration Inhibitory Factor (MIF) that interacts with the human MIF receptor CD74
    Yoonsang Cho
    Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    J Biol Chem 282:23447-56. 2007
    ....
  40. ncbi Increased Fructose 2,6-bisphosphate in peripheral blood mononuclear cells of patients with diabetes
    Toshiya Atsumi
    Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo 060 0812, Japan
    Endocr J 54:517-20. 2007
    ..These data suggest that hyperglycemia increases intracellular F2,6BP in immune cells. These findings may help to clarify the impaired function in immune cells in patients with diabetes...
  41. 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...
  42. pmc A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia
    Michael A McDevitt
    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    J Exp Med 203:1185-96. 2006
    ..These data suggest that polymorphisms at the MIF locus may influence the levels of MIF produced in the innate response to malaria infection and the likelihood of anemic complications...
  43. pmc Macrophage migration inhibitory factor and autism spectrum disorders
    Elena L Grigorenko
    Child Study Center, Department ofPsychology, Yale University, New Haven, Connecticut 06519, USA
    Pediatrics 122:e438-45. 2008
    ....
  44. pmc Cooperative regulation of non-small cell lung carcinoma angiogenic potential by macrophage migration inhibitory factor and its homolog, D-dopachrome tautomerase
    Arlixer M Coleman
    Microbiology and Immunology Program, School of Medicine, University of Louisville, Louisville, KY 40202, USA
    J Immunol 181:2330-7. 2008
    ..This is the first demonstration of a biological role for D-DT, and its synergism with MIF suggests that the combined therapeutic targeting of both family members may enhance current anti-MIF-based therapies...
  45. 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...
  46. 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...
  47. 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...
  48. pmc Impaired macrophage migration inhibitory factor-AMP-activated protein kinase activation and ischemic recovery in the senescent heart
    Heng Ma
    Department of Physiology, Fourth Military Medical University, Xi an, China
    Circulation 122:282-92. 2010
    ..Elderly patients are more sensitive than younger patients to myocardial ischemia, which results in higher mortality. We investigated how aging affects the cardioprotective AMP-activated protein kinase (AMPK) signaling pathway...
  49. 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...
  50. pmc Macrophage migration inhibitory factor: critical role in obesity, insulin resistance, and associated comorbidities
    Robert Kleemann
    Department of Biosciences, Gaubius Laboratory, TNO Quality of Life, Zernikedreef 9, 2301 CE Leiden, The Netherlands
    Mediators Inflamm 2010:610479. 2010
    ..This is a comprehensive summary of our current knowledge on the role of MIF in obesity and obesity-associated comorbidities, based on human clinical data as well as animal models of disease...
  51. pmc Elevated levels of macrophage migration inhibitory factor (MIF) in the plasma of HIV-1-infected patients and in HIV-1-infected cell cultures: a relevant role on viral replication
    Eduardo G Regis
    Laboratory on Thymus Research, Oswaldo Cruz Institute FIOCRUZ, Rio de Janeiro, RJ, Brazil
    Virology 399:31-8. 2010
    ..Our results show that HIV-1 induces MIF secretion and suggest that MIF influences the HIV-1 biology through activation of HIV-1 LTR...
  52. pmc Pure Hemozoin is inflammatory in vivo and activates the NALP3 inflammasome via release of uric acid
    Jason W Griffith
    Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA
    J Immunol 183:5208-20. 2009
    ..These data suggest that uric acid is released during malaria infection and may serve to augment the initial host response to hemozoin via activation of the NALP3 inflammasome...
  53. pmc Macrophage migration inhibitory factor anti-thrombin III complexes are decreased in bladder cancer patient serum: Complex formation as a mechanism of inactivation
    Katherine L Meyer-Siegler
    Bay Pines VA Healthcare System, Research and Development, Bay Pines, FL 33744, USA
    Cancer Lett 290:49-57. 2010
    ..These data suggest that increased circulating levels of bioactive MIF are present in bladder cancer patient serum...
  54. 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...
  55. 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
    ....
  56. pmc The influence of macrophage migration inhibitory factor gene polymorphisms on outcome from community-acquired pneumonia
    Sachin Yende
    Clinical Research, Investigation, and Systems Modeling of Acute Illness Laboratory, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    FASEB J 23:2403-11. 2009
    ..These data indicate that polymorphisms associated with higher MIF expression may have a beneficial effect in community-acquired pneumonia...
  57. 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...
  58. 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 Grants30

  1. Mental Stress Ischemia: Prognosis and Genetic Influences
    Arshed A Quyyumi; Fiscal Year: 2013
    ....
  2. A TOLERANCE APPROACH TO XENOTRANSPLANTATION
    David H Sachs; Fiscal Year: 2013
    ..abstract_text> ..
  3. CENTER FOR THE STUDY OF INFLAMMATORY BOWEL DISEASE
    Ramnik J Xavier; Fiscal Year: 2013
    ..These goals are fostered by Pilot/Feasibility Study awards which support new research initiatives as well as an enrichment program of seminars, workshops and symposia. ..
  4. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  5. 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. ..
  6. Role of Mkp-1 in pneumonia
    LYN MILLER WANCKET; Fiscal Year: 2013
    ..The overall research goal of this proposal is to understand the role of the endogenous immune suppressor Mkp-1 in both primary and secondary bacterial pneumonia, including implications for treatment. ..
  7. 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. ..
  8. 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. ..
  9. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  10. Linking the physical and chemical characteristics of Qdots to their toxicity
    TERRANCE JAMES KAVANAGH; Fiscal Year: 2013
    ..These advances can then be used in safe design and manufacturing of nanomaterials so as to maximize their utility for many applications. ..
  11. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  12. Development and Evaluation of Dual Compartment Combination Microbicides
    ROBERT WALTER BUCKHEIT; Fiscal Year: 2013
    ..Through our industrial partnership with ImQuest Pharmaceuticals our methodology and products will have an immediate outlet to further clinical development. ..