Richard Bucala

Yale-New Haven Hospital, New Haven, Connecticut, United States

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Publications (369)2124.84 Total impact

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    ABSTRACT: Infection with mosquito-borne West Nile virus (WNV) is usually asymptomatic but can lead to severe WNV encephalitis. The innate cytokine, macrophage migration inhibitory factor (MIF), is elevated in patients with WNV encephalitis and promotes viral neuroinvasion and mortality in animal models. In a case-control study, we examined functional polymorphisms in the MIF locus in a cohort of 454 North American patients with neuroinvasive WNV disease and found patients homozygous for high-expression MIF alleles to be >20-fold ( p= 0.008) more likely to have WNV encephalitis. These data indicate that MIF is an important determinant of severity of WNV neuropathogenesis and may be a therapeutic target.
    No preview · Article · Feb 2016 · Cytokine
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    ABSTRACT: The immunoregulatory cytokine macrophage migration inhibitory factor (MIF) is encoded in a functionally polymorphic locus that is linked to the susceptibility of autoimmune and infectious diseases. The MIF promoter contains a 4-nucleotide microsatellite polymorphism (-794 CATT) that repeats 5 to 8 times in the locus, with greater numbers of repeats associated with higher mRNA levels. Because there is no information about the transcriptional regulation of these common alleles, we used oligonucleotide affinity chromatography and liquid chromatography-mass spectrometry to identify nuclear proteins that interact with the -794 CATT5-8 site. An analysis of monocyte nuclear lysates revealed that the transcription factor ICBP90 (also known as UHRF1) is the major protein interacting with the MIF microsatellite. We found that ICBP90 is essential for MIF transcription from monocytes/macrophages, B and T lymphocytes, and synovial fibroblasts, and TLR-induced MIF transcription is regulated in an ICBP90- and -794 CATT5-8 length-dependent manner. Whole-genome transcription analysis of ICBP90 shRNA-treated rheumatoid synoviocytes uncovered a subset of proinflammatory and immune response genes that overlapped with those regulated by MIF shRNA. In addition, the expression levels of ICBP90 and MIF were correlated in joint synovia from patients with rheumatoid arthritis. These findings identify ICBP90 as a key regulator of MIF transcription and provide functional insight into the regulation of the polymorphic MIF locus.
    Preview · Article · Jan 2016 · Journal of Clinical Investigation
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    ABSTRACT: Copy number variations (CNVs) have been implicated in human diseases. However, it remains unclear how they affect immune dysfunction and autoimmune diseases, including rheumatoid arthritis (RA). Here, we identified a novel leukocyte-specific protein 1 (LSP1) deletion variant for RA susceptibility located in 11p15.5. We replicated that the copy number of LSP1 gene is significantly lower in patients with RA, which correlates positively with LSP1 protein expression levels. Differentially expressed genes in Lsp1-deficient primary T cells represent cell motility and immune and cytokine responses. Functional assays demonstrated that LSP1, induced by T-cell receptor activation, negatively regulates T-cell migration by reducing ERK activation in vitro. In mice with T-cell-dependent chronic inflammation, loss of Lsp1 promotes migration of T cells into the target tissues as well as draining lymph nodes, exacerbating disease severity. Moreover, patients with RA show diminished expression of LSP1 in peripheral T cells with increased migratory capacity, suggesting that the defect in LSP1 signaling lowers the threshold for T-cell activation. To our knowledge, our work is the first to demonstrate how CNVs result in immune dysfunction and a disease phenotype. Particularly, our data highlight the importance of LSP1 CNVs and LSP1 insufficiency in the pathogenesis of RA and provide previously unidentified insights into the mechanisms underlying T-cell migration toward the inflamed synovium in RA.
    No preview · Article · Nov 2015 · Proceedings of the National Academy of Sciences
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    ABSTRACT: Pathologic proliferation of mesangial and parietal epithelial cells (PECs) is a hallmark of various glomerulonephritides. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that mediates inflammation by engagement of a receptor complex involving the components CD74, CD44, CXCR2, and CXCR4. The proliferative effects of MIF may involve CD74 together with the coreceptor and PEC activation marker CD44. Herein, we analyzed the effects of local glomerular MIF/CD74/CD44 signaling in proliferative glomerulonephritides. MIF, CD74, and CD44 were upregulated in the glomeruli of patients and mice with proliferative glomerulonephritides. During disease, CD74 and CD44 were expressed de novo in PECs and colocalized in both PECs and mesangial cells. Stress stimuli induced MIF secretion from glomerular cells in vitro and in vivo, in particular from podocytes, and MIF stimulation induced proliferation of PECs and mesangial cells via CD74. In murine crescentic GN, Mif-deficient mice were almost completely protected from glomerular injury, the development of cellular crescents, and the activation and proliferation of PECs and mesangial cells, whereas wild-type mice were not. Bone marrow reconstitution studies showed that deficiency of both nonmyeloid and bone marrow-derived Mif reduced glomerular cell proliferation and injury. In contrast to wild-type mice, Cd74-deficient mice also were protected from glomerular injury and ensuing activation and proliferation of PECs and mesangial cells. Our data suggest a novel molecular mechanism and glomerular cell crosstalk by which local upregulation of MIF and its receptor complex CD74/CD44 mediate glomerular injury and pathologic proliferation in GN.
    Full-text · Article · Oct 2015 · Journal of the American Society of Nephrology
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    ABSTRACT: Background: Pathological features of Alzheimer's disease (AD) include aggregation of amyloid beta (Aβ) and tau protein. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has been implicated in the toxicity of aggregated Aβ. It remains unclear whether MIF affects hyperphosphorylation and aggregation of tau. Methods: The effects of MIF deficiency in tau hyperphosphorylation were examined in Mif (-/-) mice receiving intracerebroventricular (ICV) injection of streptozotocin (STZ) and in APP/PS1 transgenic mice mated with Mif (-/-) mice. MIF expression and astrocyte activation were evaluated in ICV-STZ mice using immunofluorescence staining. Cultured primary astrocytes were treated with high glucose to mimic STZ function in vitro, and the condition medium (CM) was collected. The level of tau hyperphosphorylation in neurons treated with the astrocyte CM was determined using Western blotting. Results: MIF deficiency attenuated tau hyperphosphorylation in mice. ICV injection of STZ increased astrocyte activation and MIF expression in the hippocampus. MIF deficiency attenuated astrocyte activation in ICV-STZ mice. CM from high glucose-treated WT astrocytes increased tau hyperphosphorylation in cultured primary neurons, an effect absent from Mif (-/-) astrocytes and WT astrocytes treated with the MIF inhibitor ISO-1. ISO-1 had no direct effect on tau phosphorylation in cultured primary neurons. Conclusions: These results suggest that MIF deficiency is associated with reduced astrocyte activation and tau hyperphosphorylation in the mouse AD models tested. Inhibition of MIF and MIF-induced astrocyte activation may be useful in AD prevention and therapy.
    Preview · Article · Sep 2015 · Journal of Neuroinflammation
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    ABSTRACT: For more than 15 years, the tautomerase active site of macrophage migration inhibitory factor (MIF) and its catalytic residue Pro1 have been being targeted for the development of therapeutics that block activation of its cell surface receptor, CD74. Neither the biological role of the MIF catalytic site nor the mechanistic details of CD74 activation are well understood. The inherently unstable structure of CD74 remains the biggest obstacle in structural studies with MIF for understanding the basis of CD74 activation. Using a novel approach, we elucidate the mechanistic details that control activation of CD74 by MIF surface residues and identify structural parameters of inhibitors that reduce CD74 biological activation. We also find that N-terminal mutants located deep in the catalytic site affect surface residues immediately outside the catalytic site, which are responsible for reduction of CD74 activation.
    No preview · Article · Sep 2015 · Chemistry & biology
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    ABSTRACT: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and has been implicated in inflammatory diseases. However, little is known about the regulation of MIF in adipose tissue and its impact on wound healing. The aim of this study was to investigate MIF expression in inflamed adipose and determine its role in inflammatory cell recruitment and wound healing. Adipose tissue was harvested from subcutaneous adipose tissue layers of 24 healthy subjects and from adipose tissue adjacent to acutely inflamed wounds of 21 patients undergoing wound debridement. MIF protein and mRNA expression were measured by ELISA and RT-PCR. Cell-specific MIF expression was visualized by immunohistochemistry. The functional role of MIF in cell recruitment was investigated by a chemotaxis assay and by flow cytometry of labeled macrophages that were injected into Mif-/-and wildtype mice. Wound healing was evaluated by an in vitro scratch assay on human fibroblast monolayers. MIF protein levels of native adipose tissue and supernatants from acutely inflamed wounds were significantly elevated when compared to healthy controls. MIF mRNA expression was increased in acutely inflamed adipose tissue indicating the activation of MIF gene transcription in response to adipose tissue inflammation. MIF is expressed in mature adipocytes and in infiltrated macrophages. Peripheral blood mononuclear cell migration was significantly increased towards supernatants derived from inflamed adipose tissue. This effect was partially abrogated by MIF-neutralizing antibodies. Moreover, when compared to wildtype mice, Mif-/-mice showed reduced infiltration of labeled macrophages into LPS-stimulated epididymal fat pads in vivo. Finally, MIF antibodies partially neutralized the detrimental effect of MIF on fibroblast wound healing. Our results indicate that increased MIF expression and rapid activation of the MIF gene in fat tissue adjacent to acute wound healing disorders may play a role in cell recruitment to the site of inflammation and wound healing.
    Preview · Article · Sep 2015 · PLoS ONE
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    ABSTRACT: Evidence from clinical studies and animal models show that inflammation can lead to the development of depression. Macrophage migration inhibitory factor (MIF) is an important multifunctional cytokine that is synthesized by several cell types in the brain. MIF can increase production of other cytokines, activates cyclooxygenase (COX)-2 and can counter-regulate anti-inflammatory effects of glucocorticoids. Increased plasma levels of MIF are associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and depressive symptoms in patients. In contrast, MIF knockout (KO) mice have been found to exhibit increased depressive-like behaviour. The exact role for MIF in depression is therefore still controversial. To further understand the role of MIF in depression, we studied depressive-like behaviour in congenic male and female MIF KO mice and wild-type (WT) littermates and the associated neurobiological mechanisms underlying the behavioural outcome. MIF KO and WT mice were tested for spontaneous locomotor activity in the open-field test, anhedonia-like behaviour in the sucrose preference test (SPT), as well as behavioural despair in the forced swim test (FST) and tail suspension test (TST). Brain and serum levels of cytokines, the enzymes COX-2 and indoleamine-2,3-dioxygenase (IDO) and the glucocorticoid hormone corticosterone were measured by RT-qPCR and/or high-sensitivity electrochemiluminescence-based multiplex immunoassays. Monoamines and metabolites were examined using HPLC. We found that MIF KO mice of both sexes displayed decreased depressive-like behaviour as measured in the FST. In the TST, a similar, but non-significant, trend was also found. IFN-γ levels were decreased, and dopamine metabolism increased in MIF KO mice. Decreased brain IFN-γ levels predicted higher striatal dopamine levels, and high dopamine levels in turn were associated with reduced depressive-like behaviour. In the SPT, there was a sex-specific discrepancy, where male MIF KO mice showed reduced anhedonia-like behaviour whereas female KO mice displayed increased anhedonia-like behaviour. Our results suggest that this relates to the increased corticosterone levels detected in female, but not male, MIF KO mice. Our findings support that MIF is involved in the generation of depressive-like symptoms, potentially by the effects of IFN-γ on dopamine metabolism. Our data further suggests a sex-specific regulation of the involved mechanisms.
    Full-text · Article · Sep 2015 · Journal of Neuroinflammation
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    ABSTRACT: Cardiac surgery involves myocardial ischemia/reperfusion (I/R) with potentially deleterious consequences. Macrophage migration inhibitory factor (MIF) is a stress-regulating chemokine-like cytokine that protects against I/R-damage, but functional links with its homolog D-dopachrome tautomerase (MIF-2) and the circulating soluble receptor CD74 (sCD74) are unknown. Here, we investigate the role of MIF, MIF-2, sCD74, and MIF genotypes in patients scheduled for elective single or complex surgical procedures such as coronary artery bypass-grafting or valve-replacement. MIF and MIF-2 levels significantly increased intra-operatively, whereas measured sCD74 decreased correspondingly. Circulating sCD74/MIF complexes were detectable in 50% of patients and enhanced MIF's antioxidant activity. Intra-operative MIF levels were independently associated with a reduced risk for the development of atrial fibrillation (AF) (odds-ratio 0.99 (0.98-1.00);p=0.007). Circulating levels of MIF-2, but not MIF, were associated with an increased frequency of organ-dysfunction and predicted the occurrence of AF (area-under-the-curve (AUC)=0.663;p=0.041) and pneumonia (AUC=0.708;p=0.040). Patients with a high-expression MIF-genotype exhibited a reduced incidence of organ-dysfunction compared to patients with low-expression MIF-genotypes (3 vs. 25;p=0.042). The current study comprehensively highlights the kinetics and clinical relevance of MIF family proteins and the MIF-genotype in cardiac surgery patients. Our findings suggest that increased MIF levels during cardiac surgery feature organ-protective properties during myocardial I/R, while the soluble MIF receptor sCD74 may enhance MIF's antioxidant activity. In contrast, high MIF-2 levels are predictive of the development of organ-dysfunction. Importantly, we provide first evidence for a gene-phenotype relationship between variant MIF-alleles and clinical outcome in cardiac surgery patients.
    Full-text · Article · Aug 2015 · Antioxidants & Redox Signaling
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    ABSTRACT: Arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) cause large-scale epidemics of severe musculoskeletal disease and have been progressively expanding their global distribution. Since its introduction in July 2014, CHIKV now circulates in the United States. The hallmark of alphavirus disease is crippling pain and inflammation of the joints, a similar immunopathology to rheumatoid arthritis. The use of glycans as novel therapeutics is an area of research that has increased in recent years. Here, we describe the promising therapeutic potential of the glycosaminoglycan (GAG)-like molecule pentosan polysulfate (PPS) to alleviate virus-induced arthritis. Mouse models of RRV and CHIKV disease were used to characterize the extent of cartilage damage in infection and investigate the potential of PPS to treat disease. This was assessed using histological analysis, real-time PCR, and fluorescence-activated cell sorting (FACS). Alphaviral infection resulted in cartilage destruction, the severity of which was alleviated by PPS therapy during RRV and CHIKV clinical disease. The reduction in cartilage damage corresponded with a significant reduction in immune infiltrates. Using multiplex bead arrays, PPS treatment was found to have significantly increased the anti-inflammatory cytokine interleukin-10 and reduced proinflammatory cytokines, typically correlated with disease severity. Furthermore, we reveal that the severe RRV-induced joint pathology, including thinning of articular cartilage and loss of proteoglycans in the cartilage matrix, was diminished with treatment. PPS is a promising new therapy for alphavirus-induced arthritis, acting to preserve the cartilage matrix, which is damaged during alphavirus infection. Overall, the data demonstrate the potential of glycotherapeutics as a new class of treatment for infectious arthritis.
    No preview · Article · May 2015 · Journal of Virology
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    Maor Sauler · Richard Bucala · Patty J Lee
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    ABSTRACT: The prevalence of many common respiratory disorders, including pneumonia, Chronic Obstructive Lung Disease, pulmonary fibrosis and lung cancer increases with age. Little is known of the host factors that may predispose individuals to such diseases. Macrophage Migration Inhibitory Factor (MIF) is a potent upstream regulator of the immune system. MIF is encoded by variant alleles that occur commonly in the population. In addition to its role as a pro-inflammatory cytokine, a growing body of literature demonstrates that MIF influences diverse molecular processes important for the maintenance of cellular homeostasis, and may influence the incidence or clinical manifestations of a variety of chronic diseases. This review highlights the biologic properties of MIF and its implication in age-related lung disease. Copyright © 2014, American Journal of Physiology - Lung Cellular and Molecular Physiology.
    Preview · Article · May 2015 · AJP Lung Cellular and Molecular Physiology
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    ABSTRACT: Mortality from pneumococcal pneumonia remains high despite antibiotic therapy, highlighting the pathogenic potential for host inflammation. We demonstrate that macrophage migration inhibitory factor (MIF), an innate immune mediator, is detrimental for survival as well as lung pathology, inflammatory cellular infiltration, and bacterial burden in a mouse model of pneumococcal pneumonia despite being necessary for clearance from the nasopharynx. Treatment of animals with a small molecule inhibitor of MIF improves survival by reducing inflammation and improving bacterial control. Our work demonstrates that MIF modulates beneficial vs. detrimental inflammatory responses in the host-pneumococcal interaction and is a potential target for therapeutic modulation. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail:
    No preview · Article · May 2015 · The Journal of Infectious Diseases
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    ABSTRACT: The rising number of obese individuals has become a major burden to the healthcare systems worldwide. Obesity includes not only the increase of adipose tissue mass but importantly also the altered cellular functions that collectively lead to a chronic state of adipose tissue inflammation, insulin resistance and impaired wound healing. Adipose tissue undergoing chronic inflammation shows altered cytokine expression and an accumulation of adipose tissue macrophages (ATM). The macrophage migration inhibitory factor (MIF) superfamily consists of MIF and the recently identified homolog D-dopachrome tautomerase (D-DT or MIF-2). MIF and D-DT, which both bind to the CD74/CD44 receptor complex, are differentially expressed in adipose tissue and have distinct roles in adipogenesis. MIF positively correlates with obesity as well as insulin resistance and contributes to adipose tissue inflammation by modulating ATM functions. D-DT, however, is negatively correlated with obesity and reverses glucose intolerance. In this review, their respective roles in adipose tissue homeostasis, adipose tissue inflammation, insulin resistance and impaired wound healing will be reviewed.
    Preview · Article · May 2015
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    ABSTRACT: The cytokine macrophage migration inhibitory factor (MIF) possesses unique tautomerase enzymatic activity which contributes to MIF’s biological functional activity. In this study, we investigated the effects of blocking the hydrophobic active site of MIF’s tautomerase activity in the pathogenesis of lung cancer. To address this, we initially established a Lewis lung carcinoma (LLC) murine model in Mif-KO and wild-type (WT) mice and compared tumour growth in a knock-in mouse model expressing a mutant MIF lacking enzymatic activity (Mif/P1G). Primary tumour growth was significantly attenuated in both Mif-KO and Mif/P1G mice compared with WT mice. We subsequently undertook a structure-based, virtual screen to identify putative small molecular weight inhibitors specific for MIF’s tautomerase enzymatic active site. From primary and secondary screens, the inhibitor, SCD-19 was identified which significantly attenuated MIF’s tautomerase enzymatic activity in vitro and in biological functional screens. In the LLC murine model, SCD-19, given intraperitoneally at the time of tumour inoculation, was found to significantly reduce primary tumour volume by 90% (p<0.001) compared with the control treatment. To better replicate the human disease scenario, SCD-19 was given when the tumour was palpable (at day 7, post-tumour inoculation) and again, treatment was found to significantly reduce tumour volume by 81% p<0.001) compared with the control treatment. In this paper, we identify a novel inhibitor which blocks the hydrophobic pocket of MIF, which houses it’s specific tautomerase enzymatic activity, and demonstrate that targeting this unique active site significantly attenuates lung cancer growth in in vitro and in in vivo systems.
    Full-text · Article · Apr 2015 · Molecular Medicine
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    Richard Bucala · Idit Shachar
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    ABSTRACT: Molecules that link innate and adaptive immunity and regulate immune response in health and disease are now the focus of many studies. This review discusses CD74 and its ligand macrophage migration inhibitory factor (MIF), and their central position in linking these two components of the immune response by controlling survival of macrophages and B cells.
    Full-text · Article · Feb 2015 · Mini Reviews in Medicinal Chemistry
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    ABSTRACT: Macrophage migration inhibitory factor (MIF) enhances activation of leukocytes, endothelial cells and fibroblast-like synoviocytes (FLS), thereby contributing to the pathogenesis of rheumatoid arthritis (RA). A MIF promoter polymorphism in RA patients resulted in higher serum MIF concentration and worsens bone erosion; controversially current literature reported an inhibitory role of MIF in osteoclast formation. The controversial suggested that the precise role of MIF and its putative receptor CD74 in osteoclastogenesis and RA bone erosion, mediated by locally formed osteoclasts in response to receptor activator of NF-κB ligand (RANKL), is unclear. We reported that in an in vivo K/BxN serum transfer arthritis, reduced clinical and histological arthritis in MIF(-/-) and CD74(-/-) mice were accompanied by a virtual absence of osteoclasts at the synovium-bone interface and reduced osteoclast-related gene expression. Furthermore, in vitro osteoclast formation and osteoclast-related gene expression were significantly reduced in MIF(-/-) cells via decreasing RANKL-induced phosphorylation of NF-κB-p65 and ERK1/2. This was supported by a similar reduction of osteoclastogenesis observed in CD74(-/-) cells. Furthermore, a MIF blockade reduced RANKL-induced osteoclastogenesis via deregulating RANKL-mediated NF-κB and NFATc1 transcription factor activation. These data indicate that MIF and CD74 facilitate RANKL-induced osteoclastogenesis, and suggest that MIF contributes directly to bone erosion, as well as inflammation, in RA. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Full-text · Article · Jan 2015 · Cytokine
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    ABSTRACT: Exposure to hyperoxia results in acute lung injury. A pathogenic consequence of hyperoxia is endothelial injury. Macrophage migration inhibitory factor (MIF) has a cytoprotective effect on lung endothelial cells; however, the mechanism is uncertain. We postulate that the MIF receptor CD74 mediates this protective effect. Using adult wild-type (WT), MIF-deficient (Mif(-/-)), CD74-deficient (Cd74(-/-)) mice and MIF receptor inhibitor treated mice, we report that MIF deficiency or inhibition of MIF receptor binding results in increased sensitivity to hyperoxia. Mif(-/-) and Cd74(-/-) mice demonstrated decreased median survival following hyperoxia compared to WT mice. Mif(-/-) mice demonstrated an increase in bronchoalveolar protein (48%) and lactate dehydrogenase (LDH) (68%) following 72 hours of hyperoxia. Similarly, treatment with MIF receptor antagonist resulted in a 59% and 91% increase in bronchoalveolar lavage protein and LDH, respectively. Inhibition of CD74 in primary murine lung endothelial cells (MLECs) abrogated the protective effect of MIF, including decreased hyperoxia-mediated AKT phosphorylation and a 20% reduction in the antiapoptotic effect of exogenous MIF. Treatment with MIF decreased hyperoxia-mediated H2AX phosphorylation in a CD74-dependent manner. These data suggest that therapeutic manipulation of the MIF-CD74 axis in lung endothelial cells may be a novel approach to protect against acute oxidative stress.-Sauler, M., Zhang, Y., Min, J.-n., Leng, L., Shan, P., Roberts, S., Jorgensen, W. L., Bucala, R., Lee, P. J. Endothelial CD74 mediates macrophage migration inhibitory factor protection in hyperoxic lung injury. © FASEB.
    No preview · Article · Jan 2015 · The FASEB Journal
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    ABSTRACT: The study examined Hypothalamus-Pituitary-Adrenal (HPA) axis and inflammatory signaling in 206 youth with histories of prenatal drug exposure and self-reported histories of maltreatment. Youth with histories of severe neglect showed elevated levels of cortisol, the end product of the HPA axis, in comparison to youth with lower or minimal levels of neglect. Histories of severe neglect also were associated with increased levels of Macrophage Migration Inhibitory Factor (MIF), a cytokine known to be intricately involved in HPA axis regulation. Salivary MIF levels also were positively associated with youth age and prenatal drug exposure. These MIF and cortisol alterations may signal pathophysiological disruptions in the neuro-endocrine and immune systems, which may lead to trajectories of increased disease risk among vulnerable youth. Our findings also provide preliminary support for the validity and reliability of a noninvasive salivary assessment of MIF. © 2014 Wiley Periodicals, Inc. Dev Psychobiol.
    Full-text · Article · Jan 2015 · Developmental Psychobiology
  • Bin Wu · Yang Song · Lin Leng · Richard Bucala · Liang-Jing Lu
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    ABSTRACT: This paper aims to explore the cost-effectiveness of reduced doses or discontinuation of etanercept biosimilar (Yisaipu) in patients with moderately active rheumatoid arthritis (RA). A discrete event simulation model was developed to project lifetime medical costs and quality-adjusted life-years (QALYs) in moderately active RA. Strategies starting with Yisaipu 50 mg/week for nine months following Yisaipu 50 mg/week, 25 mg/week or MTX maintenance were compared. Resource consumptions related to RA were estimated from the perspective of the Chinese health care system. An endpoint of the American College of Rheumatology (ACR) response was used to estimate the utility scores. Uncertainty in model parameters was analysed by sensitivity analyses. When using ACR as an endpoint for determining successful treatment, strategies starting with Yisaipu 50 mg/week for nine months following Yisaipu 50 mg/week or 25 mg/week maintenance showed the greatest number of QALYs gained (nearly 11.9 and 11.3 with or without rituximab after the failure of Yisaipu, respectively). If decision makers use a threshold of 3×the per capita GDP of China or Shanghai City in 2012, then the strategies most likely to be cost-effective are initial treatment with Yisaipu 50 mg/week for nine months following MTX maintenance and Yisaipu 25 mg/week maintenance, respectively. Results were sensitive to the cost of Yisaipu. The analysis indicates that, in China, replacing branded etanercept with Yisaipu is likely to be a cost-effective strategy in patients with moderately active RA.
    No preview · Article · Dec 2014 · Clinical and experimental rheumatology
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    ABSTRACT: Recruitment of peripheral monocytes to the liver is a key contributor to the response to injury. MIF can act as a chemokine and cytokine, regulating innate immune responses in many tissues and cell types. We hypothesized that MIF contributes to the progression of CCl4-induced hepatic fibrosis by regulating recruitment of SAM. SAMs dynamically regulate HSC activation and ECM degradation. To gain insight into the role of MIF in progression of liver fibrosis, we investigated markers of fibrosis and immune responses after chronic CCl4 administration to female C57BL/6 and MIF(-/-) mice. Chronic CCl4 exposure increased activation of HSC in WT mice, indicated by increased expression of αSMA mRNA and protein, as well as mRNA for collagen 1α1; these responses were blunted in female MIF(-/-) mice. Despite lower activation of HSC in MIF(-/-) mice, accumulation of ECM was similar in WT and MIF(-/-)mice, suggesting a decreased rate of ECM degradation. Recruitment of SAMs was lower in MIF(-/-) mice compared with WT mice, both in their initial inflammatory phenotype, as well as in the later phase as proresolution macrophages. The decreased presence of resolution macrophages was associated with lower expression of MMP13 in MIF(-/-) mice. Taken together, these data indicate that MIF-dependent recruitment of SAMs contributes to degradation of ECM via MMP13, highlighting the importance of appropriate recruitment and phenotypic profile of macrophages in the resolution of fibrosis.
    No preview · Article · Nov 2014 · Journal of Leukocyte Biology

Publication Stats

20k Citations
2,124.84 Total Impact Points


  • 2003-2016
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
    • The Ohio State University
      Columbus, Ohio, United States
  • 1996-2015
    • Yale University
      • • Department of Internal Medicine
      • • Section of Rheumatology
      • • School of Medicine
      New Haven, Connecticut, United States
    • Albert Einstein College of Medicine
      • Department of Pathology
      New York City, New York, United States
  • 2013
    • University at Buffalo, The State University of New York
      Buffalo, New York, United States
  • 2012
    • Rutgers, The State University of New Jersey
      • Department of Genetics
      Нью-Брансуик, New Jersey, United States
  • 2009-2012
    • University of Louisville
      • Division of Medical Oncology and Hematology
      Louisville, Kentucky, United States
  • 2010
    • Weizmann Institute of Science
      • Department of Immunology
  • 2006
    • Hokkaido University
      • Department of Medicine II
      Sapporo-shi, Hokkaido, Japan
  • 2005
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
    • Kurume University
      • Division of Nephrology
      Куруме, Fukuoka, Japan
  • 1984-2005
    • The Rockefeller University
      • • Laboratory of Cellular Physiology and Immunology
      • • Laboratory of Investigative Dermatology
      New York City, New York, United States
  • 2004
    • Hokuriku University
      Kanazawa, Ishikawa, Japan
  • 1999-2004
    • University of California, San Francisco
      • Division of Hospital Medicine
      San Francisco, CA, United States
    • Louisiana State University Health Sciences Center New Orleans
      New Orleans, Louisiana, United States
  • 2002
    • Gracie Square Hospital, New York, NY
      New York City, New York, United States
  • 1998
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
    • Burke Medical Research Institute New York
      New York, New York, United States
  • 1995
    • New York Medical College
      New York, New York, United States
    • Nara Medical University
      • Department of Internal Medicine
      Kashihara, Nara, Japan
    • Southwest Institute for Medical Research
      El Paso, Texas, United States
  • 1985
    • CUNY Graduate Center
      New York City, New York, United States