MIF
Macrophage migration inhibitory factor (EC 5.3.2.1) (MIF) (Glycosylation-inhibiting factor) (GIF) (L-dopachrome isomerase) (L-dopachrome tautomerase) (EC 5.3.3.12) (Phenylpyruvate tautomerase) [GLIF] [MMIF]
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The beneficial functions of mesenchymal stem cells (MSCs) decline with age, limiting their therapeutic efficacy for myocardial infarction (MI). Macrophage migration inhibitory factor (MIF) promotes cell proliferation and survival. We investigated whether MIF overexpression could rejuvenate aged MSCs and increase their therapeutic efficacy in MI. Young and aged MSCs were isolated from the bone marrow of young and aged donors. Young MSCs, aged MSCs, and MIF-overexpressing aged MSCs were transplanted into the peri-infarct region in a rat MI model. Aged MSCs exhibited a lower proliferative capacity, lower MIF level, greater cell size, greater senescence-associated-β-galactosidase activity, and weaker paracrine effects than young MSCs. Knocking down MIF in young MSCs induced cellular senescence, whereas overexpressing MIF in aged MSCs reduced cellular senescence. MIF rejuvenated aged MSCs by activating autophagy, an effect largely reversed by the autophagy inhibitor 3-methyladenine. MIF-overexpressing aged MSCs induced angiogenesis and prevented cardiomyocyte apoptosis to a greater extent than aged MSCs, and had improved heart function and cell survival more effectively than aged MSCs four weeks after MI. Thus, MIF rejuvenated aged MSCs by activating autophagy and enhanced their therapeutic efficacy in MI, suggesting a novel MSC-based therapeutic strategy for cardiovascular diseases in the aged population.
MeSH Terms
- Adolescent
- Aged
- Aged, 80 and over
- Aging
- Animals
- Animals, Newborn
- Cellular Senescence
- Humans
- Macrophage Migration-Inhibitory Factors
- Mesenchymal Stem Cell Transplantation
- Mesenchymal Stem Cells
- Myocardial Infarction
- Myocardium
- Myocytes, Cardiac
- Rats
- Rats, Sprague-Dawley
- Young Adult
Keywords
- macrophage migration inhibitory factor
- mesenchymal stem cells
- myocardial infarction
- rejuvenation
- senescence
The age-induced, exponential accumulation of mitochondrial DNA (mtDNA) deletion mutations contributes to muscle fiber loss. The causes of these mutations are not known. Systemic inflammation is associated with decreased muscle mass in older adults and is implicated in the formation of sporadic mtDNA deletions. Macrophage migration inhibitory factor knockout (MIF-KO) mice are long-lived with decreased inflammation. We hypothesized that aged MIF-KO mice would have lower mtDNA deletion frequencies and fewer electron transport chain (ETC) deficient fibers. We measured mtDNA copy number and mutation frequency as well as the number and length of ETC deficient fibers in 22-month old MIF-KO and F2 hybrid control mice. We also measured mtDNA copy number and deletion frequency in female UM-HET3 mice, a strain whose lifespan matches the MIF-KO mice. We did not observe a significant effect of MIF ablation on muscle mtDNA deletion frequency. There was a significantly lower mtDNA copy number in the MIF-KO mice and the lifespan-matched UM-HET3 mice compared to the F2 hybrids, suggesting the importance of genetic background in mtDNA copy number control. Our data do not support a definitive role for MIF in age-induced mtDNA deletions.
MeSH Terms
- Animals
- Cellular Senescence
- DNA Copy Number Variations
- DNA, Mitochondrial
- Intramolecular Oxidoreductases
- Longevity
- Macrophage Migration-Inhibitory Factors
- Macrophages
- Mice
- Mice, Knockout
Keywords
- Macrophage migration inhibitory factor
- Mitochondrial DNA
- Mutation
- Skeletal muscle
Previous studies have suggested that macrophage migration inhibitory factor (MIF) serves an important role in hearing function; however, the underlying mechanism remains unclear. In the present study, perivascular‑resident macrophage‑like melanocytes (PVM/Ms) from the stria vascularis of the lateral cochlear wall in young and aged mice were isolated. The mRNA and protein expression levels of MIF were determined using reverse transcription‑quantitative polymerase chain reaction analysis, and western blotting, respectively. MIF expression was knocked down in vitro and in vivo using small interfering RNA. Cell viability was determined using an MTT assay and cell apoptosis was determined using flow cytometry analysis. The hearing ability was assessed through the auditory brain stem response in vivo. The results of the current study demonstrated that the expression of MIF was significantly downregulated in aged mice compared with in young mice. Furthermore, the viability of PVM/Ms in aged mice was significantly decreased and the number of apoptotic PVM/Ms was significantly increased compared with that in young mice. Further studies demonstrated that the MIF knockdown accentuated hearing loss in young mice as compared with the scramble control group. In addition, the MIF knockdown in PVM/Ms significantly inhibited cell viability and lead to a significant increase in the apoptotic cell number as compared with the control group. In summary, these results revealed that the MIF knockdown significantly accentuates hearing loss in young mice in vivo, and significantly inhibits the viability and induces the apoptosis of PVM/Ms in vitro. Thus, the results of the present study may provide a novel potential therapeutic approach and prevention method for presbycusis.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Cell Count
- Cell Survival
- Cochlea
- Down-Regulation
- Gene Knockdown Techniques
- Hearing Loss
- Macrophage Migration-Inhibitory Factors
- Macrophages
- Melanocytes
- Mice, Inbred C57BL
Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons in the brain and spinal cord. It has been suggested that the toxicity of mutant SOD1 results from its misfolding and accumulation on the cytoplasmic faces of intracellular organelles, including the mitochondria and endoplasmic reticulum (ER) of ALS-affected tissues. Recently, macrophage migration inhibitory factor (MIF) was shown to directly inhibit the accumulation of misfolded SOD1 and its binding to intracellular membranes, but the role of endogenous MIF in modulating SOD1 misfolding in vivo remains unknown. To elucidate this role, we bred MIF-deficient mice with SOD1(G85R) mice, which express a dismutase-inactive mutant of SOD1 and are considered a model of familial ALS. We found that the accumulation of misfolded SOD1, its association with mitochondrial and ER membranes, and the levels of sedimentable insoluble SOD1 aggregates were significantly higher in the spinal cords of SOD1(G85R)-MIF(-/-) mice than in their SOD1(G85R)-MIF( / ) littermates. Moreover, increasing MIF expression in neuronal cultures inhibited the accumulation of misfolded SOD1 and rescued from mutant SOD1-induced cell death. In contrast, the complete elimination of endogenous MIF accelerated disease onset and late disease progression and shortened the lifespan of the SOD1(G85R) mutant mice. These findings indicate that MIF plays a significant role in the folding and misfolding of SOD1 in vivo, and they have implications for the potential therapeutic role of up-regulating MIF within the nervous system to modulate the selective accumulation of misfolded SOD1.
MeSH Terms
- Amyotrophic Lateral Sclerosis
- Animals
- Cell Death
- Disease Models, Animal
- Endoplasmic Reticulum
- Female
- Gene Expression
- Humans
- Intramolecular Oxidoreductases
- Longevity
- Macrophage Migration-Inhibitory Factors
- Male
- Mice
- Mice, Knockout
- Mitochondria
- Mutation
- Neurons
- Primary Cell Culture
- Protein Aggregates
- Protein Folding
- Spinal Cord
- Superoxide Dismutase-1
Keywords
- ALS
- MIF
- misfolded SOD1
- mutant SOD1
- mutant SOD1 mouse
Aging leads to unfavorable geometric and functional sequelae in the heart. The proinflammatory cytokine macrophage migration inhibitory factor (MIF) plays a role in the maintenance of cardiac homeostasis under stress conditions although its impact in cardiac aging remains elusive. This study was designed to evaluate the role of MIF in aging-induced cardiac anomalies and the underlying mechanism involved. Cardiac geometry, contractile and intracellular Ca(2 ) properties were examined in young (3-4 mo) or old (24 mo) wild type and MIF knockout (MIF(-/-)) mice. Our data revealed that MIF knockout exacerbated aging-induced unfavorable structural and functional changes in the heart. The detrimental effect of MIF knockout was associated with accentuated loss in cardiac autophagy with aging. Aging promoted cardiac inflammation, the effect was attenuated by MIF knockout. Intriguingly, aging-induced unfavorable responses were reversed by treatment with the autophagy inducer rapamycin, with improved myocardial ATP availability in aged WT and MIF(-/-) mice. Using an in vitro model of senescence, MIF knockdown exacerbated doxorubicin-induced premature senescence in H9C2 myoblasts, the effect was ablated by MIF replenishment. Our data indicated that MIF knockout exacerbates aging-induced cardiac remodeling and functional anomalies despite improved inflammation, probably through attenuating loss of autophagy and ATP availability in the heart.
MeSH Terms
- Adenosine Triphosphate
- Aging
- Animals
- Autophagy
- Cell Line
- Cellular Senescence
- Heart
- Inflammation
- Intramolecular Oxidoreductases
- Macrophage Migration-Inhibitory Factors
- Macrophages
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Myocardium
- Sirolimus
- Ventricular Remodeling
The aging lung is increasingly susceptible to infectious disease. Changes in pulmonary physiology and function are common in older populations, and in those older than 60 years, pneumonia is the major cause of infectious death. Understanding age-related changes in the innate and adaptive immune systems, and how they affect both pulmonary and systemic responses to pulmonary challenge are critical to the development of novel therapeutic strategies for the treatment of the elderly patient. In this observational study, we examined age-associated differences in inflammatory responses to pulmonary challenge with cell wall components from Gram-positive bacteria. Thus, male Sprague-Dawley rats, aged 6 months or greater than 18 months (approximating humans of 20 and 55-65 years), were challenged, intratracheally, with lipoteichoic acid and peptidoglycan. Cellular and cytokine evaluations were performed on both bronchoalveolar lavage fluid (BAL) and plasma, 24 h post-challenge. The plasma concentration of free thyroxine, a marker of severity in non-thyroidal illness, was also evaluated. The older animals had an increased chemotactic gradient in favor of the airspaces, which was associated with a greater accumulation of neutrophils and protein. Furthermore, macrophage migration inhibitory factor (MIF), an inflammatory mediator and putative biomarker in acute lung injury, was increased in both the plasma and BAL of the older, but not young animals. Conversely, plasma free thyroxine, a natural inhibitor of MIF, was decreased in the older animals. These findings identify age-associated inflammatory/metabolic changes following pulmonary challenge that it may be possible to manipulate to improve outcome in the older, critically ill patient.
MeSH Terms
- Adult
- Age Factors
- Aged
- Animals
- Chemotaxis
- Humans
- Lipopolysaccharides
- Macrophage Migration-Inhibitory Factors
- Male
- Middle Aged
- Neutrophils
- Peptidoglycan
- Pneumonia
- Rats
- Rats, Sprague-Dawley
- Teichoic Acids
- Thyroxine
- Young Adult
Keywords
- Acute lung injury
- Aging
- Pneumonia
- Thyroxine
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 proinflammatory 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 lung diseases. This review highlights the biological properties of MIF and its implication in age-related lung disease.
MeSH Terms
- Aging
- Animals
- Cytokines
- Humans
- Inflammation
- Intramolecular Oxidoreductases
- Lung Neoplasms
- Macrophage Migration-Inhibitory Factors
- Mice
- Pneumonia, Bacterial
- Pulmonary Disease, Chronic Obstructive
Keywords
- MIF
- innate immunity
- lung
Mesenchymal stem cells (MSCs)-based therapies have had positive outcomes in animal models of cardiovascular diseases. However, the number and function of MSCs decline with age, reducing their ability to contribute to endogenous injury repair. The potential of stem cells to restore damaged tissue in older individuals can be improved by specific pretreatment aimed at delaying senescence and improving their regenerative properties. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that modulates age-related signaling pathways, and hence is a good candidate for rejuvenative function. Bone marrow-derived mesenchymal stem cells (BM-MSCs) were isolated from young (6-month-old) or aged (24-month-old) male donor rats. Cell proliferation was measured using the CCK8 cell proliferation assay; secretion of VEGF, bFGF, HGF, and IGF was assessed by RT-qPCR and ELISA. Apoptosis was induced by hypoxia and serum deprivation (hypoxia/SD) for up to 6 hr, and examined by flow cytometry. Expression levels of AMP-activated protein kinase (AMPK) and forkhead box class O 3a (FOXO3a) were detected by Western blotting. CD74 expression was assayed using RT-qPCR, Western blotting, and immunofluorescence. In this study, we found that MSCs isolated from the bone marrow of aged rats displayed reduced proliferative capacity, impaired ability to mediate paracrine signaling, and lower resistance to hypoxia/serum deprivation-induced apoptosis, when compared to younger MSCs. Interestingly, pretreatment of aged MSCs with MIF enhanced their growth, paracrine function and survival. We detected enhanced secretion of VEGF, bFGF, HGF, and IGF from MIF-treated MSCs using ELISA. Finally, we show that hypoxia/serum deprivation-induced apoptosis is inhibited in aged MSCs following MIF exposure. Next, we found that the mechanism underlying the rejuvenating function of MIF involves increased CD74-dependent phosphorylation of AMPK and FOXO3a. Furthermore, this effect was abolished when CD74, AMPK, or FOXO3a expression was silenced using small-interfering RNAs(siRNA). MIF can rejuvenate MSCs from a state of age-induced senescence by interacting with CD74 and subsequently activating AMPK-FOXO3a signaling pathways. Pretreatment of MSCs with MIF may have important therapeutic implications in restoration or rejuvenation of endogenous bone marrow-MSCs in aged individuals.
MeSH Terms
- AMP-Activated Protein Kinases
- Aging
- Animals
- Antigens, Differentiation, B-Lymphocyte
- Apoptosis
- Bone Marrow Cells
- Cell Hypoxia
- Cell Proliferation
- Cells, Cultured
- Down-Regulation
- Forkhead Box Protein O3
- Forkhead Transcription Factors
- Histocompatibility Antigens Class II
- Intercellular Signaling Peptides and Proteins
- Intramolecular Oxidoreductases
- Macrophage Migration-Inhibitory Factors
- Male
- Mesenchymal Stem Cells
- Myocardium
- Paracrine Communication
- Phosphorylation
- RNA Interference
- Rats
- Rats, Sprague-Dawley
- Signal Transduction
Hearing loss related to aging is the most common sensory disorder among elderly individuals. Macrophage migration inhibitory factor (MIF) is a multi-functional molecule. The aim of this study was to identify the role of MIF in the inner ear. MIF-deficient mice (MIF(-/-) mice) of BALB/c background and wild-type BALB/c mice were used in this study. Expression of MIF protein in the inner ear was examined by immunohistochemistry in wild-type mice (WT). The hearing function was assessed by the click-evoked auditory brainstem response in both MIF(-/-) mice and WT at 1, 3, 6, 9, 12, and 18months of age. Morphological examination of the cochlea was also performed using scanning electron microscopy and light microscopy. MIF was observed in the spiral ligament, stria vascularis, Reissner's membrane, spiral ganglion cells (SGCs), saccular macula, and membranous labyrinth. The MIF(-/-) mice had a significant hearing loss as compared with the WT at 9, 12, and 18months of age. In the MIF(-/-) mice, scanning electron microscopy showed that the outer cochlear hair cells were affected, but that the inner cochlear hair cells were relatively well preserved. The number of SGCs was lower in the MIF(-/-) mice. MIF was strongly expressed in the mouse inner ear. Older MIF(-/-) mice showed accelerated age-related hearing loss and morphological inner ear abnormalities. These findings suggest that MIF plays an important role in the inner ear of mice.
MeSH Terms
- Aging
- Animals
- Auditory Threshold
- Ear, Inner
- Evoked Potentials, Auditory, Brain Stem
- Hearing Loss
- Immunohistochemistry
- Intramolecular Oxidoreductases
- Macrophage Migration-Inhibitory Factors
- Mice, Inbred BALB C
- Mice, Knockout
- Microscopy, Electron, Scanning
Keywords
- cochlea
- ear
- hair cell
- hearing loss
- macrophage migration inhibitory factor
- spiral ganglion cells
The pathogenesis of chronic obstructive pulmonary disease (COPD) remains poorly understood. Cellular senescence and apoptosis contribute to the development of COPD; however, crucial regulators of these underlying mechanisms remain unknown. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that antagonizes both apoptosis and premature senescence and may be important in the pathogenesis of COPD. This study examines the role of MIF in the pathogenesis of COPD. Mice deficient in MIF (Mif(-/-)) or the MIF receptor CD74 (Cd74(-/-)) and wild-type (WT) controls were aged for 6 mo. Both Mif(-/-) and Cd74(-/-) mice developed spontaneous emphysema by 6 mo of age compared with WT mice as measured by lung volume and chord length. This was associated with activation of the senescent pathway markers p53/21 and p16. Following exposure to cigarette smoke, Mif(-/-) mice were more susceptible to the development of COPD and apoptosis compared with WT mice. MIF plasma concentrations were measured in a cohort of 224 human participants. Within a subgroup of older current and former smokers (n = 72), MIF concentrations were significantly lower in those with COPD [8.8, 95%CI (6.7-11.0)] compared with those who did not exhibit COPD [12.7 ng/ml, 95%CI (10.6-14.8)]. Our results suggest that both MIF and the MIF receptor CD74 are required for maintenance of normal alveolar structure in mice and that decreases in MIF are associated with COPD in human subjects.
MeSH Terms
- Adolescent
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Animals
- Apoptosis
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- Cyclin-Dependent Kinase Inhibitor p21
- Emphysema
- Female
- Humans
- Intramolecular Oxidoreductases
- Lung
- Macrophage Migration-Inhibitory Factors
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Middle Aged
- Pulmonary Disease, Chronic Obstructive
- Receptors, Immunologic
- Smoke
- Smoking
- Tobacco
- Tumor Suppressor Protein p53
- Young Adult
Keywords
- CD74
- COPD
- MIF
- apoptosis
- emphysema
- senescence
The beneficial effects of testosterone treatment (TT) are debated. Double-blinded, placebo-controlled study of six months TT (gel) in 54 men aged 60-78 with bioavailable testosterone (BioT) <7.3 nmol/L and waist >94 cm randomized to TT (50-100 mg/day, n = 20), placebo (n = 18), or strength training (ST) (n = 16) for 24 weeks. Moreover, the ST group was randomized to TT (n = 7) or placebo (n = 9) after 12 weeks. Chemokines (MIF, MCP-1, and MIP-1 α ) and lean body mass (LBM), total, central, extremity, visceral, and subcutaneous (SAT) fat mass established by DXA and MRI. Results. From 0 to 24 weeks, MIF and SAT decreased during ST placebo versus placebo, whereas BioT and LBM were unchanged. TT decreased fat mass (total, central, extremity, and SAT) and increased BioT and LBM versus placebo. MIF levels increased during TT versus ST placebo. ST TT decreased fat mass (total, central, and extremity) and increased BioT and LBM versus placebo. From 12 to 24 weeks, MCP-1 levels increased during TT versus placebo and MCP-1 levels decreased during ST placebo versus placebo. ST placebo was associated with decreased MIF levels suggesting decreased inflammatory activity. TT may be associated with increased inflammatory activity.
MeSH Terms
- Absorptiometry, Photon
- Aged
- Aging
- Body Composition
- Chemokine CCL2
- Chemokine CCL3
- Chemokines
- Double-Blind Method
- Gels
- Humans
- Inflammation
- Intramolecular Oxidoreductases
- Macrophage Migration-Inhibitory Factors
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Resistance Training
- Testosterone
- Time Factors
- Treatment Outcome
Microvascular injury and increased vascular leakage are prominent features of radiation-induced lung injury (RILI), and often follow cancer-associated thoracic irradiation. Our previous studies demonstrated that polymorphisms in the gene (MIF) encoding macrophage migratory inhibition factor (MIF), a multifunctional pleiotropic cytokine, confer susceptibility to acute inflammatory lung injury and increased vascular permeability, particularly in senescent mice. In this study, we exposed wild-type and genetically engineered mif(-/-) mice to 20 Gy single-fraction thoracic radiation to investigate the age-related role of MIF in murine RILI (mice were aged 8 wk, 8 mo, or 16 mo). Relative to 8-week-old mice, decreased MIF was observed in bronchoalveolar lavage fluid and lung tissue of 8- to 16-month-old wild-type mice. In addition, radiated 8- to 16-month-old mif(-/-) mice exhibited significantly decreased bronchoalveolar lavage fluid total antioxidant concentrations with progressive age-related decreases in the nuclear expression of NF-E2-related factor-2 (Nrf2), a transcription factor involved in antioxidant gene up-regulation in response to reactive oxygen species. This was accompanied by decreases in both protein concentrations (NQO1, GCLC, and heme oxygenase-1) and mRNA concentrations (Gpx1, Prdx1, and Txn1) of Nrf2-influenced antioxidant gene targets. In addition, MIF-silenced (short, interfering RNA) human lung endothelial cells failed to express Nrf2 after oxidative (H2O2) challenge, an effect reversed by recombinant MIF administration. However, treatment with an antioxidant (glutathione reduced ester), but not an Nrf2 substrate (N-acetyl cysteine), protected aged mif(-/-) mice from RILI. 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.
MeSH Terms
- Acute Lung Injury
- Aging
- Animals
- Bronchoalveolar Lavage Fluid
- Cells, Cultured
- Gamma Rays
- Heme Oxygenase-1
- Humans
- Hydrogen Peroxide
- Intramolecular Oxidoreductases
- Macrophage Migration-Inhibitory Factors
- Membrane Proteins
- Mice
- Mice, Knockout
- NAD(P)H Dehydrogenase (Quinone)
- NF-E2-Related Factor 2
- Oxidants
- Radiation Injuries, Experimental