Vitamin E is a MIF Inhibitor

June 14, 2017 | Autor: A. Kulkarni-almeida | Categoria: Enzyme Inhibitors, Humans, Vitamin E, Biochemical, Protein Conformation, Biochemistry and cell biology
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Biochemical and Biophysical Research Communications 418 (2012) 384–389

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Vitamin E is a MIF Inhibitor Bindu Hegde a,1, Prashant Vadnal b,1, Jingal Sanghavi c, Vaidehi Korde d, Asha A. Kulkarni-Almeida a, Nilesh M. Dagia b,⇑ a

The Department of High Throughput Screening, NCE-Unit of Piramal Healthcare Limited, Mumbai, Maharashtra, India The Department of Pharmacology, NCE-Unit of Piramal Healthcare Limited, Mumbai, Maharashtra, India c The Department of Discovery Analytical Sciences, NCE-Unit of Piramal Healthcare Limited, Mumbai, Maharashtra, India d The Department of Discovery Informatics, NCE-Unit of Piramal Healthcare Limited, Mumbai, Maharashtra, India b

a r t i c l e

i n f o

Article history: Received 22 December 2011 Available online 18 January 2012 Keywords: Pain Inflammation MIF Vitamin E

a b s t r a c t Macrophage migration inhibitory factor (MIF) is known to contribute to the pathogenesis of inflammatory hyperalgesia and neuropathic pain. Prior studies have shown that Vitamin E treatment is associated with attenuated hyperalgesia and reduced neuropathic pain in rodents. Given these observations, we investigated the possibility that Vitamin E is a MIF inhibitor. Dopachrome tautomerase assays revealed that Vitamin E inhibits the enzymatic activity of purified human recombinant MIF (rhMIF) in a dosedependent manner (45%, 74%, 92% and 100% inhibition at 3, 10, 30 and 100 lM, respectively). Cell-free ELISA based assays showed that Vitamin E binds onto rhMIF thereby blocking its recognition (48% inhibition at 100 lM). Circular dichroism studies indicated the Vitamin E has a strong affinity to bind to rhMIF (binding constant 19.52 ± 1.4 lM). In silico studies demonstrated that Vitamin E docks well in the active site of MIF with the long aliphatic chain of Vitamin E exhibiting strong van der Waals interactions with MIF. Most importantly, human cell-based assays revealed that Vitamin E significantly inhibits rhMIF-induced production of pro-inflammatory cytokines in a dose-dependent manner (77%, 80%, and 96% inhibition of IL-6 production, respectively, at 10, 30 and 100 lM). Taken together, these results demonstrate that Vitamin E inhibits not only the enzymatic activity of MIF but more importantly the biological function of MIF. Our findings suggest that Vitamin E may be attenuating hyperalgesia and reducing neuropathic pain at least in part by inhibiting MIF activity. Ó 2012 Elsevier Inc. All rights reserved.

1. Introduction Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with wide-ranging cellular and biological activities [1,2]. It is well-established that heightened expression of MIF plays an integral role in the pathogenesis of a variety of inflammatory and auto-immune diseases [2,3]. More recently, a growing body of evidence indicates that dysregulated levels of MIF are associated with clinical pain and contribute to the pathogenesis of pain. Indeed, (i) a significant positive correlation has been observed between the levels of MIF and period with pain symptom in subjects with paranasal sinus mucocele [4], (ii) a significant increase in MIF levels has been observed in women with endometriosis reporting pelvic

Abbreviations: BSA, bovine serum albumin; CD, circular dichroism; GOLD, Genetic Optimization for Ligand Docking; HRP, horse-radish peroxidase; IL-6, interleukin-6; ISO-F, fluorinated analog of ISO-1; MIF, macrophage migration inhibitory factor. ⇑ Corresponding author. Address: Piramal Healthcare Limited, 1 Nirlon Complex, Off. Western Express Highway, Goregaon (East), Mumbai 400063, Maharashtra, India. Fax: +91 22 30818036. E-mail address: [email protected] (N.M. Dagia). 1 These authors contributed equally to this work. 0006-291X/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2012.01.031

pain [5] and a possible role for MIF has been suggested in endometriosis-associated pain [6], (iii) spinal MIF plays a critical role in the pathogenesis of formalin-induced inflammatory pain [7] and rodent neuropathic pain-like hypersensitivity [8]. The analgesic effects of Vitamin E are well-documented. Indeed, (i) administration of Vitamin E protects rats against alcohol-induced neuropathic pain [9] and neuropathic pain produced by spinal nerve ligation [10], (ii) early co-administration of Vitamin E acetate and methylcobalamin improves thermal hyperalgesia and motor nerve conduction velocity following sciatic nerve crush injury in rats [11]. The aforementioned observations, and other findings, have led to Vitamin E being considered as an alternative therapy for pain [12]. Given the above, in this study, we investigated the hypothesis that Vitamin E possesses anti-MIF activity. 2. Materials and methods 2.1. Dopachrome tautomerase assays The procedure followed was as described earlier [13–15]. Purified recombinant human MIF synthesized as detailed elsewhere [13] was diluted in assay buffer (50 mM potassium phosphate,

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pH 6.0; 1 mM EDTA). Subsequently, 200 ll of MIF (equating to 8 ng) was aliquoted in separate wells of a 96-well plate and treated with varying concentrations of Vitamin E (alpha tocopherol E; Sigma Aldrich) for 30 min at room temperature. As a control, some wells of purified MIF were treated with the vehicle control (DMSO; Sigma Aldrich) or positive control (ISO-F; a MIF inhibitor [16] synthesized in-house at Piramal Life Sciences Limited [13]) for 30 min. at room temperature. The modified proteins were then analyzed for enzymatic activity by adding dopachrome methyl ester (20 ll per well). The absorbance was read at 475 nm using a microwell plate spectrophotometer (Molecular Devices; Sunnyvale, CA) and compared with that of the controls (i.e., untreated MIF, MIF treated with DMSO and assay buffer-containing wells). In every experiment, each treatment condition was carried out in triplicate. Furthermore, for every experiment, dopachrome methyl ester was freshly prepared. The procedure followed for the latter was as detailed elsewhere [13]. 2.2. MIF ELISAs Purified recombinant human MIF was diluted to 2.5 lg/ml in PBS. Subsequently, 200 ll of diluted MIF was aliquoted in separate wells of a 96-well plate (blocked overnight with PBS, 1% bovine serum albumin (BSA)) and treated with varying concentrations of Vitamin E for 4 h. at room temperature. As a control, some wells of purified MIF were treated with the vehicle control (DMSO) for 4 h. at room temperature. Following the incubation, the levels of human MIF in each well were quantitated using ELISA. The protocol followed was as per manufacturer’s recommendation (R&D Systems, Minneapolis, MN). Briefly, separate wells of a 96-well plate were coated with a capture antibody directed against human MIF overnight at room temperature. The next day, wells were washed and subsequently blocked in PBS, 1% BSA for 1 h. at room temperature. MIF from different wells was then added for 2 h. at room temperature. Following extensive washing, the wells were incubated with a biotinylated detection antibody directed against human MIF. After 2 h. incubation at room temperature, wells were washed and strepatavidin–horseradish peroxidase (SA–HRP) and a chromogenic substrate were added. Finally, the absorbance was read using a spectrophotometer. The concentrations of MIF in each well were calculated using MIF standards and a calibration curve. In every experiment, each treatment condition was carried out in triplicate. 2.3. Far UV circular dichroism (CD) The procedure followed was as described earlier [13]. Far-UV CD spectra of MIF were recorded at 22 °C on a Jasco J-815 spectropolarimeter equipped with a variable temperature control unit (Peltier Thermal unit). The measurements were performed (in the wavelength range 200–250 nm) in a rectangular quartz cuvette with pathlength of 1 mm at protein concentration of 11.2 lM in PBS pH 7.0 (200 ll final volume). For experiments, a concentrated stock solution (200 lM) of Vitamin E or positive control (ISO-F) was prepared by dissolving it in ethanol/PBS (1 part ethanol with 19 parts of PBS). Titration experiments were carried out through the addition of different aliquots of Vitamin E or ISO-F stock in the experimental protein sample in the cuvette. All spectra were accumulated and averaged over three scans for each measurement. A buffer blank was used to subtract buffer contributions to the CD signal of the MIF. Due to the concentrated stock solutions of Vitamin E and ISO-F prepared in ethanol/PBS, and the subsequent addition of this stock in a lower volume range to the protein sample during the titration, the effect of ethanol/PBS on the CD signal of MIF was found to be negligible. For Kd determination, all CD data were normalized by converting the CD signal (millidegrees) into

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constant values using the equation (h0  hsample)/h0, where h0 is the molar ellipticity of the protein without the ligand, and hsample is the corresponding change in the molar ellipticity of the protein for the respective addition of ligand aliquots. The normalized values obtained from the equation were then plotted versus ligand concentration (lM) and fitted to a hyperbolic curve (single binding site) using GraphPad Prism software version 3.03 for Windows (GraphPad Software; San Diego, California; USA) to get the binding constant (Kd). 2.4. Docking of Vitamin E to MIF Molecular docking was used to examine the binding of Vitamin E to MIF. The protein structure of MIF (PDB 1D 1GCZ), which was used for docking, was downloaded from Protein Data Bank (www.rcsb.org/pdb). This is a co-crystal structure of MIF with 7-Hydroxy-2-Oxo-Chromene-3-Carboxylic acid ethyl ester. The ligand (Vitamin E) was docked to 1GCZ using GOLD (Genetic Optimization for Ligand Docking) software. The procedure followed was as described earlier [13]. Vitamin E structure was downloaded from Thomson Prous as structure data file. It was converted to mol file in MOE 2010.11. Hydrogens were added to Vitamin E. It was minimized to low energy starting conformation using the MMFF94 forcefield to an RMS gradient of 0.05A. Hydrogens were added to 1GCZ and the protein was energy minimized using the CHARMM forcefield to an RMS gradient of 0.05A. All heavy atoms were constrained to their crystallographic positions during the minimization. The center of the active0 site was fixed at (48.727 35.58– 1.534) and a sphere of radius 8 Å A around this center was explored during the docking. The values of Genetic Operators were set at their default levels. 2.5. Biological assays with purified MIF Blood was collected from normal healthy volunteers after informed consent. All procedures were approved by the Ethics Committee of Piramal Life Sciences Limited. Human peripheral blood mononuclear cells were harvested using Ficoll-Hypaque density gradient centrifugation (1.077 g/ml; Sigma Aldrich) [13]. Human peripheral blood mononuclear cells were resuspended in RPMI 1640 supplemented with 10% fetal calf serum, 100 units/ml penicillin and 100 lg/ml streptomycin at 1  106 cells/ml and used for assays. Purified human MIF (200 ll at 30 ng/ml) was treated with varying concentrations of Vitamin E (10, 30 or 100 lM) or DMSO or ISO-F (positive control) for 1 h. at 37 °C. Following the incubation, 1  105 human peripheral blood mononuclear cells / well were stimulated with the Vitamin E/DMSO/ISO-F-treated MIF solution for 21 h. at 37 °C. Subsequently, supernatants were collected and stored at 70 °C until assayed for human IL-6 by ELISA as described by the manufacturer (OptiEIA ELISA sets, BD BioSciences) and detailed elsewhere [13–15]. In every experiment, each treatment condition was carried out in triplicate. Limulus amoebocyte lysate (LAL) assay indicated the presence of negligible endotoxin content (0.15 EU/30 ng of purified human MIF used for biological assays) (data not shown). 2.6. Statistical analysis For analyzing differences between two groups, Student’s T-test was used. For analyzing differences among multiple (more than two) groups, a single factor ANOVA followed by Dunnett’s multiple comparison tests or Bonferroni’s multiple pair-wise comparison tests were used (as appropriate). P values < 0.05 were considered statistically significant. Unless stated otherwise, all error bars represent standard error of mean.

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3. Results 3.1. Vitamin E inhibits the enzymatic activity of MIF In initial experiments, we investigated the MIF enzyme inhibitory activity of Vitamin E. Accordingly, dopachrome tautomerase assays were performed. Vitamin E, but not vehicle control (DMSO), inhibited the dopachrome tautomerase activity of purified recombinant human MIF in a dose-dependent manner (Fig. 1B). Of note, at 100 lM concentration Vitamin E inhibited the enzymatic activity of MIF at levels equivalent to that of ISO-F (Fig. 1B). 3.2. Vitamin E inhibits the recognition of MIF Given that modification of MIF’s tautomerase activity by a small molecule can inhibit immunoreactivity and ELISA detection [17], we sought to investigate the impact of Vitamin E on immunorecognition of MIF. Accordingly, cell-free ELISA assays were performed. Purified recombinant human MIF was incubated with varying concentrations (0.03–100 lM) of Vitamin E for 4 h. Subsequently, ELISA assays were performed. Vitamin E inhibited the ‘‘recognition’’ of purified MIF in a dose-dependent manner (Fig. 2A). Interestingly, at 100 lM concentration, Vitamin E inhibited the ‘‘recognition’’ of purified MIF at levels equivalent to that of ISO-F (Fig. 2A). 3.3. Vitamin E has a binding affinity towards MIF To assess the interaction capacity of Vitamin E with MIF, circular dichroism (CD) studies were carried out. Human MIF protein

consists of a trimeric assembly of the structure with each monomer containing two anti-parallel a-helices and six b-strands, four of which form a mixed b-sheet [18]. For a folded MIF protein, the CD spectra should show a molar ellipticity minimum at 220 nm, corresponding to a combination of a-helical and b-strand structures. Accordingly, as shown in Fig. 2B, the CD spectra of purified recombinant human MIF protein exhibited a curve typical of the MIF secondary structure (combination of a-helices and b-strands; molar ellipticity minimum seen at 217 nm). Upon addition of increasing concentration of Vitamin E, a successive decrease in the CD ellipticity of MIF protein was noticed, suggesting a complex formation between MIF and Vitamin E. Note that the change in the intensity of the CD curve could arise due to a small conformational change induced by the bound Vitamin E to MIF. Nevertheless, this curve reached a saturation point at 44 lM, and the corresponding binding constant for Vitamin E was determined to be 19.52 ± 1.4 lM (Fig. 2B). 3.4. Vitamin E shows good binding potential within the active site of MIF We next studied the docking of Vitamin E to the active site of MIF. Studies performed with ISO-F [13] were utilized for comparison. In most of the conformers, Vitamin E did not form hydrogen bonds interactions with MIF (Fig. 3). Only, in one conformer, Vitamin E formed a hydrogen bond with a residue of MIF at ASN102 (Fig. 3). Of note, this residue was observed to be at the mouth of the cavity (Fig. 3). The major contribution for the docking score of Vitamin E to MIF came from Van der Waals interactions

A

B

Fig. 1. Vitamin E inhibits the enzymatic activity of MIF (A) chemical structure of Vitamin E (B) purified recombinant human MIF was treated with varying concentrations of Vitamin E (Vit E) or 0.5% DMSO (vehicle control) or ISO-F (positive control). Following a 30 min. incubation, the modified proteins were analyzed for enzymatic activity using dopachrome methyl ester. The absorbance was read at 475 nm using a microwell plate spectrophotometer. Values are averages ± SEM from a single experiment. Results presented are representative of six separate experiments. ⁄⁄ indicates P < 0.01 compared to DMSO control. ⁄⁄⁄ indicates P < 0.001 compared to DMSO control. n.s. indicates not statistically different.

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A

B

Fig. 2. Vitamin E binds onto MIF (A) purified recombinant human MIF was treated with varying concentrations of Vitamin E (Vit E) or 0.5% DMSO (vehicle control). Following a 4 h. incubation, supernatants were collected and MIF levels estimated by ELISA. The MIF level in DMSO control group was set at 100% in every experiment and used to normalize the other data. All values except for ISO-F are averages ± SEM from a single experiment. Results presented are representative of three separate experiments. ISO-F values are historical values [13]. ⁄⁄⁄ indicates P < 0.001 compared to DMSO control. n.s. indicates not statistically different. (B) (left panel) Far UV circular dichroism scans of purified recombinant human MIF protein in the presence of Vitamin E. Arrow indicates increasing concentrations of the ligand (Vitamin E). (right panel) Binding constant for Vitamin E. Results presented are representative of n = 4 separate experiments.

(Fig. 3). Vitamin E has a long aliphatic chain, attached to two fused rings. The aliphatic chain showed strong Van der Waals interactions with MIF with the fused rings being oriented towards the solvent exposed region (Fig. 3). These observations are in contrast to the findings with ISO-F, which has a different chemotype. Notably, the major contribution to the docking score for ISO-F comes from a hydrogen bond with an essential residue of MIF at LYS32 and ASN97 [13].

treatment of human peripheral blood mononuclear cells led to production of IL-6 (Fig. 4). Pre-treatment of MIF with Vitamin E, but not vehicle control (DMSO), led to a significant and dose-dependent suppression in the induced production of IL-6 (Fig. 4). Taken together, these data clearly demonstrate that Vitamin E robustly inhibits the biological function of MIF. Of note, at 100 lM concentration, the Vitamin E-mediated inhibition of MIF biological function was significantly better than that of ISO-F.

3.5. Vitamin E robustly blocks the biological function of MIF

4. Discussion

In our earlier studies, we have demonstrated that it is important for potential MIF inhibitors to block the biological function of MIF [13–15]. Accordingly, we next probed whether Vitamin E could block the purified human MIF-induced expression of pro-inflammatory cytokines. In these experiments, purified MIF was treated with varying concentrations (3, 10, 30 and 100 lM) of Vitamin E or 0.5% DMSO. Subsequently, the treated MIF was used to stimulate human peripheral blood mononuclear cells. Following a 21 h. incubation, supernatants were collected and subjected to cytokine ELISA assays. Based on our docking analysis studies, we postulated that Vitamin E would inhibit the MIF-induced production of proinflammatory cytokines. In line with our earlier results [13], MIF

In this study, we demonstrate that Vitamin E is a MIF inhibitor. In particular, Vitamin E (i) inhibits the enzymatic activity of MIF, (ii) binds onto MIF, (iii) docks well in the active site of MIF and (iv) blocks the biological activity of MIF. These results suggest that Vitamin E may be attenuating hyperalgesia and reducing neuropathic pain at least in part by inhibiting MIF activity. Our findings of Vitamin E binding onto MIF have important implications for observations from an earlier study involving Vitamin E and MIF. Sakamoto and colleagues had concluded that Vitamin E inhibits MIF secretion from rat peritoneal macrophages [19]. To arrive at this conclusion, the authors had utilized primarily ELISA detection assays. Based on our findings, it is evident that Vitamin E can bind

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Fig. 3. Vitamin E shows good binding potential within the active site of MIF. Docking analysis of Vitamin E to MIF was performed. Binding of Vitamin E to MIF is depicted. The receptor surface around the bound ligand is shown. In the molecular surface, red corresponds to exposed region, green corresponds to hydrophobic regions and pink corresponds to polar region in the receptor. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this paper.)

Fig. 4. Vitamin E inhibits purified human MIF-induced production of IL-6. Purified human MIF was treated with varying concentrations of Vitamin E (Vit E) or 0.5% DMSO (vehicle control) or ISO-F (positive control). Subsequently, the treated MIF was used to stimulate human peripheral blood mononuclear cells. Following 21 h. incubation, supernatants were collected and subjected to IL-6 ELISA assays. The IL-6 level in DMSO control group was set at 100% in every experiment and used to normalize the other data. Values are averages ± SEM from a single experiment. Results presented are representative of four separate experiments. ⁄⁄⁄ indicates P < 0.001 compared to DMSO control. # indicates P < 0.001.

onto MIF and inhibit its immunoreactivity and ELISA detection (Fig. 2). Thus, it is conceivable that in the study by Sakamoto and colleagues Vitamin E may not necessarily have prevented the secretion of MIF; it may have only prevented the immunorecognition of MIF. Interestingly, in their Western blot analyses, Sakamoto and colleagues had found no alteration of intracellular MIF content of peritoneal macrophages by Vitamin E treatment [19]. In this regard, it is noteworthy that the release of MIF from THP-1 cells is known to occur via a non-classical pathway [20]. Reagents modulating the ABC transporter, but not protein synthesis inhibitors such as cycloheximide, are known to inhibit the release of MIF [20]. Whether Vitamin E works in a similar manner and inhibits

the release of MIF by affecting ABC transporter is currently unknown and warrants further investigation. It is noteworthy that although the MIF inhibitory activity of Vitamin E was statistically similar to that of ISO-F in enzyme assays and ELISA assays (Figs. 1B and 2A), Vitamin E-mediated blockade of MIF-induced IL-6 production was significantly better than that mediated by ISO-F (Fig. 4). A plausible explanation for this observation is that, in functional assays, ‘‘unbound’’ Vitamin E may have permeated into hPBMCs and, subsequently, robustly diminished (in comparison to ISO-F) molecular components in the MIF signal transduction pathway. Of note, Vitamin E is known to attenuate NF-jB and AP-1 activation; both are important

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components of the MIF signal transduction pathway. Irrespective of the manner in which Vitamin E inhibits induced IL-6 production – either directly by masking the ‘‘biological function-mediating’’ site of MIF or by interfering with the components of MIF signal transduction pathway – our data provide evidence that Vitamin E inhibits the biological activity of MIF. It is well established that MIF regulates its biological functions through extracellular, receptor-mediated signaling (via CD74, CXCR2, CXCR4) or endocytosis [2,21]. Given our findings that Vitamin E inhibits MIF-induced production of IL-6, it would be of interest to ascertain whether Vitamin E inhibits endocytosis of MIF and/ or MIF interaction with CD74, CXCR2 or CXCR4. Of note, preliminary findings from our laboratory indicate that CD74 does not play an important role in MIF-induced production of IL-6 from hPBMCs (manuscript in preparation; Dagia et al.). Thus, our hypothesis is that Vitamin E does not interfere with MIF-CD74 interactions. In line with this hypothesis, our preliminary circular dichroism experiments reveal that MIF conjugated with Vitamin E can still bind CD74 (Supplemental Fig. 1). However, extensive future investigation is required to completely delineate the mechanism via which Vitamin E inhibits the biological function of MIF. Clearly, an important limitation of our current study is that our in vitro findings of Vitamin E being a potent MIF inhibitor need to be translated into an in vivo experimental model of inflammatory/ neuropathic pain or a disease setting wherein MIF is known to play a critical role. In this regard, we would like to point out that MIF is known to play an integral role in the pathogenesis of auto-immune inflammatory disorders such as rheumatoid arthritis and ulcerative colitis [2,22]. Interestingly, Vitamin E treatment has been shown to (i) modulate inflammatory responses in a collagen-induced mice model of rheumatoid arthritis [23], (ii) reduce colonic mucosal injury and reduce pro-inflammatory cytokine production in an acetic acid-induced ulcerative colitis model in rats [24]. Further, a water soluble derivative of Vitamin E has been shown to be efficacious in the rat TNBS-model of colitis [25]. Thus, our findings suggest that Vitamin E may be eliciting its anti-inflammatory effects, at least in part, by attenuating the biological function of MIF. Acknowledgments We would like to thank Divya Kamath, Lyle Fonseca, Anshu Chetrapal-Kunwar and Mahesh Kumar Reddy for expert technical assistance. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.bbrc.2012.01.031. References [1] J.A. Baugh, R. Bucala, Macrophage migration inhibitory factor, Crit. Care Med. 20 (2002) S27–S35. [2] E.F. Morand, M. Leech, J. Bernhagen, MIF: a new cytokine link between rheumatoid arthritis and atherosclerosis, Nat. Rev. Drug Discov. 5 (2006) 399– 410. [3] A.Y. Hoi, M.N. Iskander, E.F. Morand, Macrophage migration inhibitory factor: a therapeutic target across inflammatory diseases, Inflamm. Allergy Drug Targets 6 (2007) 183–190. [4] S. Kariya, M. Okano, K. Aoji, T. Nakashima, N. Kasai, T. Onoda, K. Nishizaki, P.A. Schachern, S. Cureoglu, M.M. Paparella, Role of macrophage migration inhibitory factor in paranasal sinus mucocele, Am. J. Rhinol. 19 (2005) 554– 559.

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