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1Department of Physiology and Functional Genomics and McKnight Brain Institute and 2Department of Anesthesiology, University of Florida, Gainesville, Florida; 3Yale University School of Medicine, New Haven, Connecticut; and 4Department of Biochemistry and Molecular Cell Biology, University Hospital of the Rheinische-Westfälische Technische Hochschule Aachen University, Aachen, Germany
Submitted 12 May 2005; accepted in final form 26 October 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). MIF cloning and sequencing studies have revealed that MIF is a 12.5-kDa protein with 115 amino acids (Bernhagen et al. 1994). Furthermore, MIF is ubiquitously expressed in immune and nonimmune tissues and has widespread actions in the immune, endocrine, and nervous systems (Fingerle-Rowson and Bucala 2001; Nishihira 2000). For example, in the immune and endocrine systems MIF promotes inflammation, counteracts the immunosuppressive effects of glucocorticoids, stimulates insulin secretion, stimulates glycolysis, and suppresses inhibin production (Bloom and Bennett 1966; Calandra et al. 1995; Fingerle-Rowson and Bucala 2001; Fingerle-Rowson et al. 2003). In the nervous system, MIF is constitutively expressed in neurons within the hypothalamus, cortex, hippocampus, and pons (Bacher et al. 1998) and has been implicated to have a number of different roles. These include the modulation of nitric oxide and prostaglandin production, a stimulatory role in catecholamine metabolism, and the regulation of neuronal sensitivity to glucocorticoids (Fingerle-Rowson and Bucala 2001; Fingerle-Rowson et al. 2003).
There have been a number of studies on the cellular mechanisms by which MIF exerts these effects and it appears that MIF exhibits both extracellular and intracellular modes of action. First—in true cytokine fashion—it is clear that MIF binds to a cell surface CD74 binding protein (Leng et al. 2003), an association that results in activation of ERK MAP kinase and increased production of PGE2 (Leng et al. 2003). In addition, other studies indicate that MIF can be internalized from the extracellular milieu in a receptor-independent manner, interact with c-Jun–activating binding protein (JAB-1), and consequently inhibit JAB-1 function (Kleemann et al. 2000). The identification of these different modes of action has led to the idea that MIF may have a dual role in controlling cell function: as an extracellular cytokine and an intracellular enzyme (Mitchell 2004). With regard to enzymatic actions it is known that the MIF molecule exhibits distinct tautomerase and thiol-oxidoreductase activities. MIF can catalyze the tautomerization of phenylpyruvate and nonphysiological substrates such as D-dopachrome (Rosengren et al. 1997), and it has been established that the N-terminal proline residue of MIF is critical for this tautomerase activity (Bendrat et al. 1997; Lubetsky et al. 1999). By contrast, the thiol-protein oxidoreductase (TPOR) activity of MIF is exerted by cysteines at residues 57 and 60 of the MIF molecule (Kleemann et al. 1998), and one potential consequence of an increase in TPOR activity is scavenging of reactive oxygen species (ROS) and blockade of oxidant-mediated intracellular actions (Nguyen et al. 2003b; Sun et al. 2004).
Our interest in MIF stems from its interactions with the peptide angiotensin II (Ang II). First, we demonstrated that Ang II increases the intracellular levels (but not secretion) of MIF in neurons cultured from newborn rat hypothalamus and brain stem (Sun et al. 2004). Subsequently, we demonstrated that MIF exhibits differential effects on neuronal activity. Intracellular (but not extracellular) application of concentrations of MIF that exceed 8 nM elicits decreases in basal neuronal firing, whereas lower concentrations of MIF (about 0.8 nM) depress the chronotropic action of Ang II (Sun et al. 2004). The latter finding indicates that MIF may serve as a negative regulator of the neuronal actions of Ang II (Sun et al. 2004). In addition, the inhibitory action of MIF on Ang II's chronotropic actions appears to involve the TPOR activity of the MIF molecule and possible scavenging of ROS (Sun et al. 2004). In the present study we have focused on understanding the fundamental membrane mechanisms by which MIF depresses basal neuronal firing. Specifically, we have investigated the effects of MIF on neuronal outward K+ currents, changes of which contribute to alterations in neuronal firing (Sun et al. 2005; Wang et al. 1997). Thus to provide the first insight into the actions of MIF on neuronal membrane ionic currents, we have investigated the effects of MIF on both the delayed rectifier K+ current (IKv) and the A-type K+ current (IA), and the role of the TPOR activity of MIF and ROS in any observed effects.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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One-day-old Sprague–Dawley (SD) rats were obtained from our breeding colony, which originated from Charles River Laboratories (Wilmington, MA). Dulbecco's modified Eagle's medium (DMEM) was obtained from Invitrogen (Grand Island, NY). Crystallized trypsin was from Worthington Biochemicals (Freehold, NJ). Rabbit anti-rat MIF antibody was purchased from Torrey Pines Biolabs (Houston, TX). Plasma-derived horse serum (PDHS), deoxyribonuclease I (DNase I), 
-cytosine arabinoside (ARC), 4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron), and all other chemicals were obtained from Sigma Chemical (St. Louis, MO). Mouse recombinant MIF (rMIF), P1S-MIF, and C60S-MIF mutants were prepared from an Escherichia coli expression system and purified free of endotoxin by C8 chromatography as described previously (Bernhagen et al. 1994; Kleemann et al. 1999). Mouse MIF differs from rat MIF by a single amino acid substitution (mMIF:asn54, rMIF:ser54) that, to date, has not been found to affect the influence of the bioactivity or immunoreactivity of the protein in different murine assays (Bacher et al. 1997; Bernhagen et al. 1994). D-Dopachrome tautomerase (DCT), which shares 27% sequence identity with MIF and is essentially identical in three-dimensional architecture, was prepared by PCR cloning from mouse cDNA, and its structural fidelity was established by DNA sequencing. The recombinant protein was purified from an E. coli expression system by sequential Mono-Q and C8 column FPLC followed by slow refolding from DTT/urea. These procedures closely followed those described previously for recombinant MIF (Bernhagen et al. 1994). The peptide fragments of rat MIF (Sakai et al. 1994), MIF-(50–65), and C57S/C60S-MIF-(50–65) were synthesized by the Tufts University Core Facility (Boston, MA). These peptides were unmodified at the N and C termini. Structures are as follows. MIF-(50–65): [H]-F-S-G-T-S-D-P-C-A-L-C-S-L-H-S-I-[OH]; C57S/C60S-MIF-(50–65): [H]-F-S-G-T-S-D-P-S-A-L-S-S-L-H-S-I-[OH].
Preparation of neuronal cultures
Neuronal cocultures were prepared from the brain stem and a hypothalamic block of newborn SD rats as described previously (Sumners et al. 1991). Trypsin (375 U/ml) and DNase I (496 U/ml)–dissociated cells were resuspended in DMEM containing 10% PDHS and plated on poly-L-lysine–precoated 35-mm Nunc plastic tissue culture dishes. After the cells were grown for 3 days at 37°C in a humidified incubator with 95% air-5% CO2, they were exposed to 1 µM ARC for 2 days in fresh DMEM containing 10% PDHS. Then ARC was removed and the cells were incubated with DMEM (10% PDHS) for a further 9–12 days before use. At the time of use, cultures consisted of about 90% neurons and about 10% astrocyte glia, as determined by immunofluorescent staining with antibodies against neurofilament proteins and glial fibrillary acidic proteins (Sumners et al. 1994).
Electrophysiological recordings
Electrophysiological studies were carried out in neurons as previously described (Kang et al. 1994; Zhu et al. 2000). Potassium current recordings were performed in the whole cell configuration of the patch-clamp technique using Axopatch 200B amplifier (Axon Instruments). Cell capacitance and the series resistance were minimized electronically. Current recordings were filtered at 1 kHz (–3 dB frequency filter) and digitized on-line at 3 kHz using a DigiData 1200A interface (Axon Instruments). Voltage-clamp experimental protocols and off-line data analysis were performed using the software program pCLAMP 8.0 (Axon Instruments). The patch pipettes (6–8 M
) were filled with solution containing (in mM) 130 KCl, 2 MgCl2, 0.25 CaCl2, 1.0 ATP, 8 dextrose, 0.1 GTP, 10 N-2-hydroxyethyl-piperazine-N'-2-ethanesulfonic acid (HEPES), and 5 ethylene glycol-bis (-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) (pH 7.2 with KOH).The superfusate solution used to measure IKv contained (in mM) 137 NaCl, 5.4 KCl, 2 MgSO4, 1.35 CaCl2, 0.3 NaH2PO4, 10 dextrose, 10 HEPES, 0.3 CdCl2, and 0.0015 tetrodotoxin (TTX) (pH 7.4 with NaOH). The superfusate solution used to measure IA contained (in mM) 137 tetraethylammonium chloride (TEA), 5.4 KCl, 2 MgSO4, 1.35 CaCl2, 0.3 NaH2PO4, 10 dextrose, 10 HEPES, 0.3 CdCl2, and 0.0015 TTX (pH 7.4 with NaOH). The intracellular perfusion of MIF was initiated 5 min after establishing of the whole cell configuration. This time was sufficient to stabilize variations in the amplitude of potassium current caused by experimental perturbations. All experiments were carried out at room temperature (22–23°C).
Total K+ current was recorded by stepping from –80 to +10 mV for 100 ms every minute. IKv was measured directly by stepping from a holding potential of –40 to +10 mV for 100 ms. To inactivate IA, depolarizing prepulses to –40 mV from the holding potential of –70 mV were applied for 50 ms (Zhu et al. 2000). For total K+ current and IKv, current amplitudes were measured at 50 ms from the onset of the test pulse. Current density was derived by dividing current amplitude (pA) by membrane capacitance (pF), which was measured by using the Membrane test of pCLAMP 8.0. The average cell capacitance for neurons used in this study was 29.4 ± 1.2 pF (n = 110, range from 12 to 68 pF). IA was elicited by depolarization of the membrane potential to +42.5 mV for 100 ms from a holding potential of –110 mV every minute (Wang et al. 1997). IA amplitude was measured as the peak current during the depolarizing pulse.
Drug applications
rMIF, MIF peptides, or anti-MIF antibodies were dissolved/diluted in pipette solution and injected intracellularly by the patch pipette as detailed previously (Sun et al. 2004; Zhu et al. 2000). In brief, a side-arm pipette holder was attached to the head stage of the Axopatch. One side arm was used to supply suction for seal formation, and a second side arm was used to advance a very fine polyethylene catheter (PE-50) down the inside of the patch pipette. Neurons were allowed to stabilize for 5 min after establishment of the whole cell configuration. Next, control (baseline) measurements were made for 5 min, and after this a pipette solution (5 µl) containing either rMIF, MIF mutants, MIF peptides, anti-MIF antibodies, or DCT was injected into the tip of the recording electrode by the PE-50 tube. From the electrode tip, the proteins, peptides, and antibodies were allowed to diffuse into the neuron and measurements of K+ were made. Care was taken not to overperfuse the neuron, and this was monitored electronically by the Axopatch 200B and on the television monitor. Thus the concentrations of proteins, peptides, and antibodies that are given in the RESULTS refer to the amounts injected at the pipette tip, and so are likely higher than the amounts that reach the site of action.
Data analyses
Results are expressed as means ± SE. Statistical significance was evaluated with one-way ANOVA and paired Student's t-test. Differences were considered significant at P < 0.05; n refers to the number of cells examined.
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RESULTS |
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In previous studies we demonstrated that intracellular, but not extracellular, application of rMIF (8–80 nM) produces a depression of basal neuronal firing in a concentration-dependent manner (Sun et al. 2004). An increase in neuronal outward K+ currents (IKv, IA) and/or decrease in inward Ca2+ currents may contribute to the depression of basal neuronal firing. Thus in the first set of experiments we tested the effects of rMIF on neuronal IKv. Intracellular application of rMIF (80 nM) produced a significant increase in IKv in nearly 80–90% of the neurons tested. This effect became apparent by 3 min, increased slowly, and reached a maximum at about 20–30 min after the start of rMIF administration (Fig. 1). The change in IKv current density (pA/pF) was from 31.58 ± 2.36 (means ± SE) in controls to 41.88 ± 3.76 in rMIF (80 nM)–treated neurons (P < 0.01) (Fig. 2). Interestingly, lower concentrations of rMIF (0.8–8 nM) failed to alter IKv (Fig. 2). Because 8 nM rMIF decreases basal neuronal firing (Sun et al. 2004), these data may suggest that other mechanisms, in addition to IKv, may mediate the depressant effect of rMIF on basal neuronal firing. In addition, our data indicate that rMIF (80 nM) that had been denatured by boiling for 20 min did not alter IKv (Fig. 2). To determine whether the augmentation of IKv by rMIF is caused by a shift in the voltage dependency of activation to more negative potentials, the voltage dependency of IKv was compared before and after treatment of neurons with rMIF. IKv density was calculated and plotted against the membrane potential. Under control conditions, IKv activated at potentials greater than –40 mV (Fig. 3). rMIF (80 nM) did not significantly change the threshold of IKv, but significantly increased the amplitude and density of IKv at all tested potentials. The increase of IKv produced by rMIF (80 nM) was abolished by simultaneous administration of MIF neutralizing antibodies (1:100 dilution; P < 0.05) but not by control IgG (1:100), indicating the specificity of this MIF action (Fig. 4).
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Our previous studies indicated that the inhibitory effect of rMIF on Ang II's neuronal chronotropic action was mediated by the TPOR activity of the MIF molecule (Sun et al. 2004). Here, our first objective was to investigate whether the stimulatory action of MIF on neuronal IKv involved its TPOR or tautomerase activity. Intracellular application of MIF-(50–65), a synthetic peptide that displays the TPOR activity of MIF and has MIF-like biological activity (Nguyen et al. 2003a; Sun et al. 2004), produces an increase in neuronal IKv. The data presented in Fig. 6A demonstrate that at a concentration of 80 nM, MIF-(50–65) did not alter IKv. However, at higher concentrations of 800 nM and 8 µM, MIF-(50–65) caused a significant increase in IKv, similar to the effects of rMIF (Fig. 6A). In contrast, intracellular application of 8 µM C57S/C60S-MIF-(50–65) [C-MIF-(50–65)], which has no TPOR activity, produces no changes in IKv (Fig. 6A). A role for a thiol-protein oxidoreductase function in this MIF action on neuronal IKv was further suggested by the use of two mutant MIF molecules. P1S-MIF, in which the proline at position 1 is substituted by serine and which displays TPOR activity, lacks tautomerase activity (Bendrat et al. 1997). Intracellular application of P1S-MIF (80 nM) mimicked the action of rMIF on neuronal IKv (Fig. 6B). C60S-MIF, in which the cysteine at position 60 is substituted by a serine, is completely devoid of TPOR activity but retains tautomerase activity (Kleemann et al. 1999). C60S-MIF (80 nM) produced no effects on neuronal IKv after intracellular application (Fig. 6B). Finally, we examined the effects of DCT on IKv. DCT, a protein that shares 27% amino acid identity with MIF, exhibits tautomerase activity (Zhang et al. 1995). However, DCT lacks one of the two homologous cysteines (Cys60) that mediate the TPOR activity of MIF. The data presented in Fig. 6B demonstrate that DCT (80 nM) fails to alter IKv.
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), suggesting that the inhibition of this Ang II action by MIF occurs by a thiol-oxidoreductase/ROS scavenging mechanism (Sun et al. 2004). Considering the above demonstration that the MIF-induced increase in neuronal IKv is mediated by the TPOR activity of the MIF molecule, we examined whether a ROS-scavenging mechanism was involved in this MIF action. The strategy we took was to test the effect of Tiron, a cell-permeable phenolic compound of low molecular weight and scavenger of intracellular superoxide anions (Krishna et al. 1992; Yamada et al. 2003), on the MIF-induced increase in neuronal IKv. Neuronal cultures were pretreated with Tiron (1 mM) for 30 min, conditions that were previously used to scavenge superoxides in neurons in culture (Rodriguez-Martin et al. 2002). The Tiron pretreatment was followed by recordings of IKv before and after intracellular application of rMIF (80 nM). The data presented in Fig. 7 demonstrate that under these experimental conditions MIF failed to produce any changes in IKv in the Tiron-pretreated neurons. Thus the data demonstrate that a superoxide scavenger can prevent the stimulatory action of MIF on neuronal IKv.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). To help clarify the mechanisms involved in this MIF action, we have focused on studying the effects of rMIF on the membrane ionic currents that play a pivotal role in controlling the activity of neurons. In the present study we have demonstrated that rMIF, at a concentration of 
80 nM, acts intracellularly to produce a significant increase in IKv but fails to alter IA. This stimulatory action of rMIF on IKv is consistent with its inhibitory effect on neuronal firing. Although the studies presented here provide the first demonstration of MIF effects on a neuronal membrane ionic current, a number of issues are also raised. One immediate issue concerns the discrepancy between the concentration of MIF required to reduce the basal firing (about 8 nM) and that which produced an increase in IKv (80 nM). If the change in IKv is linked to the change in neuronal firing, then it is difficult to resolve the difference in the concentration of rMIF required to produce a change in each case. Because changes in neuronal firing can be achieved by alterations in the activities of other ionic channels as well, one possibility is that some of these channels have even higher sensitivity to rMIF than IKv. In this regard determination of the effects of rMIF on neuronal Ca2+ currents is a part of our ongoing studies.
The data presented here provide insight into the intracellular mechanisms by which MIF increases neuronal IKv. It is well known that MIF exhibits two major enzymatic activities: a tautomerase activity mediated through the N-terminal proline residue (Pro-1) of the molecule (Bendrat et al. 1997; Lubetsky et al. 1999; Rosengren et al. 1997) and a thiol-protein oxidoreductase activity associated with residues 57–60 (Cys-Ala-Leu-Cys) (Kleemann et al. 1998; Nguyen et al. 2003b). Our previous studies indicated that the TPOR activity is responsible for the inhibitory action of rMIF on the neuronal chronotropic effect of Ang II (Sun et al. 2004). The present data indicate that the MIF mutant P1S-MIF and the peptide MIF-(50–65), both of which exhibit TPOR activity, mimic the effects of rMIF on neuronal IKv. Conversely, the MIF mutant C60S-MIF and the MIF homologue DCT, both of which exhibit MIF-like tautomerase activity but lack TPOR activity, fail to alter neuronal IKv. Collectively, these data indicate that rMIF increases IKv by the TPOR activity within its molecule. However, an issue concerning the present data is that tenfold greater levels of MIF-(50–65) (0.8 µM) are required to increase IKv compared with rMIF (80 nM) (Fig. 6). A similar discrepancy between the effective levels of MIF-(50–65) and rMIF was observed in a different study, with respect to glucocorticoid overriding activity (Nguyen et al. 2003a). The reason for the difference in effectiveness of MIF and MIF-(50–65) may reside in the demonstration that MIF exists as a homotrimer (Nishihira 1998; Sun et al. 1996; Suzuki et al. 1996). Thus it is possible that a peptide fragment such as MIF-(50–65), even though it displays TPOR activity, may not exhibit full activity because it exists in a different conformation compared with MIF. In addition, even though MIF-(50–65) exhibits the -sheet/-turn conformation of MIF, this conformation may be labile in vivo and more prone to disturbances compared with the full-length folded polypeptide.
Although the present studies have established a role for the TPOR activity of MIF in its modulatory action on neuronal IKv, they have also provided clues as to the downstream signaling events that mediate this MIF action. Here we have focused on the role of ROS, for a number of reasons. First, one possible result of an increase in TPOR activity is to scavenge ROS. Second, our previous studies suggested that the inhibitory action of rMIF on the neuronal chronotropic action of Ang II may occur by scavenging of ROS by the TPOR activity of the MIF molecule (Sun et al. 2004). Finally, there is ample evidence that ROS can mediate the activity of membrane ion channels. For example, it has been demonstrated that the fast inactivation of certain IKv is modulated by oxidative processes (Annunziato et al. 2002), and also that ROS can alter K+ channel activity (Kourie 1998). More recently, our group has demonstrated that ROS (superoxide, but not H2O2) inhibits neuronal IKv by a direct action at Kv channels (Sun et al. 2005). Here, we have demonstrated that MIF fails to increase neuronal IKv in cells that have been exposed to a superoxide-scavenging agent. Therefore these data support the idea that rMIF increases IKv (and subsequently reduces basal neuronal firing) by scavenging ROS. Despite this finding, other intracellular actions of MIF to increase IKv (e.g., by interaction with other factors that modulate channel activity) cannot be excluded at this point.
The finding that rMIF does not produce any changes in IA was surprising, when considering that this current also has a role in neuronal activation. The reasons that MIF fails to influence the activity of IA are unknown at this point. However, one possibility is that ROS play little or no role in the regulation of IA in these cells and, if this is the case, then MIF may not be expected to influence IA.
In conclusion, these data provide the first demonstration that MIF, acting intracellularly, produces a specific modulatory action on one of the K+ currents that is the basis of the neuronal action potential and thus neuronal firing. Consequently, this action of MIF may contribute to physiological/pathological actions of this protein within the CNS.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: C. Sumners, Department of Physiology and Functional Genomics, College of Medicine, P.O. Box 100274, 1600 Southwest Archer Road, University of Florida, Gainesville, FL 32610-0274 (E-mail: csumners{at}phys.med.ufl.edu)
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REFERENCES |
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) and after () intracellular application of rMIF (80 nM). Data are means ± SE for 4 neurons.
