| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Diabetes and Hormone Center (Y.W., J.G., J.L.N.), University of Virginia, Charlottesville, Virginia 22908; and Department of Diabetes Endocrinology and Metabolism (S.-.L.L., M.A.R., R.N.), City of Hope National Medical Center, Duarte, California 91010
Address all correspondence and requests for reprints to: Jerry L. Nadler, Diabetes and Hormone Center, University of Virginia, Charlottesville, Virginia 22908. E-mail: jln2n{at}virginia.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, and interferon-
are produced primarily in macrophages and have been associated with accelerated atherosclerosis and altered vascular wall function. In this study, we evaluated the effect and mechanism of high glucose (HG) on gene expression of these cytokines in mouse peritoneal macrophages (MPM). HG led to a 2-fold increase in the mRNA expression of these cytokines, with IL-12 showing the highest activation (5.4-fold) in a time-dependent (3–12 h) and dose-dependent (10, 17.5, and 25 mmol/liter) manner. The effects were specific to HG because mannitol and 3-O-methyl-glucose had no effect on cytokine mRNA expression. HG also increased IL-12 protein accumulation from MPM. We also explored the role of induced and spontaneous diabetes on inflammatory cytokine expression in MPM. Increases in expression in MPM of multiple inflammatory cytokines, including a 20-fold increase in IL-12 mRNA, were observed in streptozotocin-induced type 1 diabetic mice as well as type 2 diabetic db/db mice, suggesting that cytokine gene expression is increased by hyperglycemia in vivo. We next explored potential mechanisms of HG-induced increases in IL-12 mRNA. HG increased the activity of protein kinase C, p38 MAPK (p38), c-Jun terminal kinase, and inhibitory-
B kinase in MPM. Furthermore, inhibitors of these signaling pathways significantly reduced HG-induced IL-12 mRNA expression in MPM. These results provide evidence for a potentially important mechanism linking elevated glucose and diabetes to inflammation. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, (1), IL-1ß (2), IL-6 (3), IL-12, and IL-18. TNF, IL-1ß (1, 2), and IL-6 are important cytokines involved in chemotaxis cell adhesion. Evidence shows that IL-12 is an important cytokine that can program T cells to develop into Th1 cells (4, 5). IL-12 and Th1 cell infiltration has emerged as an important pathway for autoimmune diabetes as well as chronic inflammation associated with atherosclerosis (5, 6). Reduction of IL-12 is associated with reduced atherosclerosis in the mouse (7, 8).
Macrophages of alloxan diabetic mice with moderate diabetes (300 mg/dl) produced significantly more IL-6 and TNF (9). Recent data have also shown that high glucose (HG) treatment activates monocytes and induces an increase in gene expression of TNF, IL-1ß, and monocyte chemoattractant protein (MCP)-1 in human THP-1 monocyte like cells (10). However, it is not clear whether HG affects cytokine expression in primary tissue macrophages. Furthermore, how HG affects cytokine gene expression in tissue macrophages has not been evaluated.
The present study was designed to examine the effect and mechanism of high glucose on mRNA expression of cytokines in mouse peritoneal macrophages (MPMs) from C57BL6 mice. We found that HG treatment time- and dose-dependently leads to a more than 2-fold increase in mRNA expression of multiple cytokines with a marked increase in IL-12 gene expression. These effects are specific to HG because mannitol and 3-O-methyl-glucose had no effect. We also studied the in vivo relevance of these findings. The mRNA expression of these cytokines is also markedly increased in MPMs from streptozotocin (STZ)-induced diabetic C57BL6 mice as well as type 2 diabetic db/db mice. This is the first study showing that HG can increase cytokine gene expression and protein production in primed macrophages. These results provide a new explanation for the inflammatory effects of HG.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B (NFB) inhibitor and NFB inhibitor control peptide from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA); and RNeasy minikit from QIAGEN (Valencia, CA). Culture media and DMEM were from American Type Culture Collection (Manassas, VA), and RPMI 1640 and Hanks’ balanced salt solution were from Invitrogen (Carlsbad, CA) All animal studies were approved by our Institutional Animal Safety Committee.
MPM isolation and culture
Mice were injected ip with 2 ml 4% thioglycollate solution. Three days later, the ascites of these mice was collected and cells were spun down, resuspended in RPMI 1640 medium containing 10% fetal bovine serum (FBS) and 100 U/ml penicillin/streptomycin, seeded, and cultured on 100-mm plates for 3 h in 5% CO2 incubator at 37 C. Nonattached cells were carefully washed away by washing cells four times with Hanks’ balanced salt solution. The attached MPMs were resuspended in the same medium as above. MPM number was counted, seeded again on 60-mm culture dishes, and incubated overnight. The attached cells comprised more than 95% MPMs as reflected by specific macrophage antibody staining.
MPM treatment
The MPMs were serum depleted from typical RPMI 1640 medium containing 10 mmol/liter D-glucose (NG) supplemented with 10% heat-inactive FBS and penicillin/streptomycin for 24 h and were then cultured in varied glucose concentration for certain periods of time. In some experiments cells were pretreated with one of the following inhibitors: calphostin C, GF-109203X, SB-202190, JNK MAPK inhibitor, or NFB inhibitor for 30 min. The cells were then incubated in basal or elevated glucose for 3 h in the presence of inhibitors.
Preparation of STZ-induced diabetic mice
A single STZ injection (freshly dissolved in saline) at dose of 280 mg/kg body weight was injected ip into C57BL6 mice. Blood glucose was measured with an Accu-Chek Advantage meter (Roche Diagnostics, Indianapolis, IN) and was expressed as milligrams per deciliter. To avoid the effect of STZ itself on cytokine expression, macrophages were isolated at least 10 or more days after STZ injection. All animal protocols were approved by the Institutional Animal Safety Committee of the University of Virginia.
RNA extraction and real-time PCR
Total RNA was extracted from cells using the RNeasy kit (QIAGEN), with deoxyribonuclease I treatment. The RNA was processed to cDNA synthesis using the SuperScript II reverse transcriptase and oligo d(T) (Invitrogen) according to the manufacturer’s protocol. The sequences of forward and reverse primers for target cytokine genes and house keeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were selected based on published sequence data from the National Center for Biotechnology Information database and previous study (11).
Primers were synthesized from Integrated DNA Technologies Inc (Coralville, IA). For quantitation, a double-stranded DNA dye, SYBR Green I (Molecular Probes Inc., Eugene, OR), was used along with AmpliTaq Gold and 0.1 µM of each primer. All reactions were performed in triplicate in iCycler iQ real-time PCR detection system (Bio-Rad Laboratories, Hercules, CA). The real-time PCR was carried out in two steps: step 1, 94 C for 10 min, one cycle, and step 2, 94 C for 15 sec, followed by 60 C for 60 sec, 45 cycles. GAPDH was used as an endogenous reference to correct for differences in the amount of total RNA added to the reaction and compensate for different levels of inhibition during reverse transcription of RNA and during PCR. Data are calculated using the 2–
CT method (12) and are presented as fold induction of transcripts for target genes normalized to GAPDH in cells treated with HG or inhibitors.
Total RNA of macrophages from db/db and control db/+ mice was extracted with Trizol Invitrogen according to manufacturer’s instructions. One microgram of total RNA was used for reverse transcription using the GeneAmp RNA PCR kit (Applied Biosystems, Foster City, CA). 18S primers were used as internal control. The software used for quantitation of PCR data were Quantity One (Bio-Rad).
Cytokine protein release measurement using ELISA
Cells were seeded on 24-well plates with each well containing 1 x 106 cells of MPMs in 1 ml medium. After serum depletion for 24 h, cells were then treated either with HG (25 mmol/liter D-glucose) or NG (10 mmol/liter D-glucose). Conditioned medium was collected in a sequential fashion (e.g. 0–16, 16–24, 24–36, and 36–60 h) with a change of 1 ml fresh medium containing HG or NG at each time point. The collected culture-conditioned medium was centrifuged to separate floating cells in the medium, and the supernatant was stored at –80 C. IL-12 protein levels were measured using a specific mouse IL-12 p40 immunoassay kit (R & D Systems, Minneapolis, MN).
Kinase activity measurement using Western blot with specific phosphoantibodies
Fifty micrograms HG-treated protein extracts were resolved on 10% SDS-polyacrylamide gel. Electrophoresis was run under constant voltage conditions. The proteins on the gel were transferred onto Immuno-Blot polyvinylidene difluoride membrane from Bio-Rad that was incubated consecutively with specific phosphoantibody and antirabbit or antimouse Ig conjugated with horseradish protein, and the protein bands were detected using enhanced chemiluminescence detection reagents from Amersham Biosciences Co. (Piscataway, NJ). The membrane was then stripped using Restore Western blot stripping buffer (Pierce Co., Rockford, IL), and the membranes were incubated with nonphosphoantibody or ß-actin and detected using enhanced chemiluminescence detection reagents. The result presented in the figures was a representative of a minimum of three experiments using three different batches of primary cultured macrophages treated with HG for different times.
Data analysis
The results are expressed as mean ± SEM from combined experiments as noted in each legend. For experiments running at one time period, the control and experimental samples are analyzed using the Student’s t test. These comparisons are based on a minimum of three experiments in triplicate per treatment. For multiple time periods of conditions, ANOVA with Duncan’s or Dunnett’s test was used.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
shows that HG dose-dependently (10, 17.5, and 25 mmol/liter) increases the mRNA expression of multiple cytokines including IL-1ß, IL-6, IL-12, IL-18, and TNF more than 2-fold over that in NG-treated macrophages. Of these cytokine genes, IL-12 mRNA expression was increased the most. D-glucose (17.5 mmol/liter) induced a 3.5-fold increase, whereas 25 mmol/liter D-glucose induced a 5.5-fold increase in IL-12 gene expression, compared with that under NG conditions (P < 0.01). HG also increases interferon- about 2-fold (data not shown). Figure 1B shows the time course of HG-induced mRNA expression of these cytokine genes, which occurred as early as 3 h, and some reached a peak at 3 h and remained elevated for 6 h after HG treatment. The HG-induced increase in mRNA expression declined at 12 h of treatment. However, the value remained elevated, compared with that under the NG conditions (Fig. 1B). At 24 h of HG treatment, the HG-induced mRNA expression of most cytokine genes returned to the value seen under NG conditions (data not shown). To examine whether high osmotic pressure plays a role in HG-induced increase in cytokine gene expression, IL-12 was taken as an example. Macrophages were treated with 10 mmol/liter D-glucose + 15 mmol/liter of mannitol or 3-O-methyl-glucose (3OMG) for 3 h, and IL-12 gene expression was measured. Figure 1C shows that supplementation with15 mmol/liter mannitol or 3OMG did not change the IL-12 gene expression, compared with that under NG conditions.
|
demonstrates that HG significantly induces IL-12 secretion at the interval of 0–16 h. We did not see increases at other intervals (data not shown). Therefore, HG treatment significantly increases both IL-12 mRNA and protein expression.
Enhanced cytokine gene expression in macrophages from STZ-induced diabetic mice and diabetic db/db mice
To test the in vivo effects of diabetes on cytokine expression, macrophages were isolated from either saline-injected control mice or STZ-injected mice. The baseline blood glucose of the mice before getting STZ was 140, 152, 141, and 161 mg/dl (mean = 148.5 ± 5.0). Thioglycollate was injected on d 8 and macrophages were isolated on d 11. The blood glucose of the STZ-induced diabetic mice at the time of euthanasia was 405, 444, 468, and 474 mg/dl (447.7 ± 15.7, P = 0.0002 vs. control mice). Macrophages from saline-injected mice were taken as controls. Thioglycollate injection did not change the value of blood glucose in C57BL6 mice with 141.1 ± 5.6 mg/dl before injection and 154.5 ± 6.4 mg/dl after injection (n = 10, P = 0.135). Figure 2A shows that hyperglycemia significantly increases mRNA expression of the cytokine genes of IL-1ß, IL-6, IL-12, IL-18, and TNF in MPMs from STZ-induced diabetic mice, compared with that in macrophages from nondiabetic control mice. Noteworthily, a marked, nearly 20-fold and 9-fold increase in IL-12 and IL-1ß mRNA expression could be seen in MPMs from STZ-induced diabetic mice. Macrophages from spontaneous type 2 diabetic db/db (8–10 wk old male) mice were also used for examining the effects of hyperglycemia on cytokine gene expression. In these experiments, macrophages from 8- to 9-wk-old male heterozygotes from same mice colony (db/+) were taken as controls. The blood glucose of the db/+ and db/db mice before being killed was 160 ± 24 and 548 ± 63 mg/dl (P < 0.01 vs. db/+), respectively. Figure 2B shows that IL-1ß expression was increased almost 2-fold (P < 0.0001), IL-6 expression was increased about 17-fold (P < 0.0001), IL-12 expression was increased about 9-fold (P < 0.0001), and TNF was increased about 1.7-fold (P = 0.0011) in macrophages from db/db mice, compared with that in macrophages from control db/+ mice. These data indicate that hyperglycemia in vivo is a potent stimulus for mRNA expression of inflammatory cytokines in macrophages.
|
Thr514) antibody and specific antiphosphorylated myristolated alanine-rich C kinase substrate (MARCKS) antibody. Figure 3A shows a time-dependent increase in PKC activity, illustrating that Thr514 phosphorylated PKC was increased at 5–10 min and a peak at 30 min of HG treatment. The density of phosphorylated MARCKS bands had a similar pattern (Fig. 3B), showing an increase at 5–10 min and a peak at 30 min of HG treatment. We then tested whether two structurally distinct PKC inhibitors, GF-109203X or calphostin C attenuated HG effects on IL-12 gene expression. After serum depletion, macrophages were pretreated with fresh RPMI 1640 medium containing GF-109203X (100 nmol/liter), calphostin C (100 nmol/liter), or vehicle control dimethylsulfoxide for 30 min. MPMs were then treated with HG or NG for 3 h. Figure 3C shows that GF-109203X or calphostin C completely inhibited HG-induced IL-12 gene expression, suggesting that PKC activation is important in HG effects on IL-12 expression. GF-109203X or calphostin C alone at concentrations studied had no significant effect on IL-12 gene expression under NG condition.
|
shows a time course of p38 MAPK activity detected by Western blot using a specific anti-phospho-p38 antibody. HG-induced p38 activity occurred as early as the 5-min treatment period and reached a peak at 10 min. ß-Actin on the stripped membrane was detected with anti-ß-actin antibody, which showed equal protein loading among different samples. We also tested the effect of the relatively specific p38 MAPK inhibitor, SB 202190. After serum depletion, macrophages were pretreated with fresh RPMI 1640 medium containing either 2 µmol/liter SB 202190 or dimethylsulfoxide vehicle for 30 min. MPMs were then treated with HG or NG for 3 h. Figure 4B shows that even though SB 202190 alone had a slight effect to increase basal IL-12 gene expression in NG, SB 202190 almost completely inhibited HG-induced IL-12 gene expression. These results suggest that p38 MAPK is also important for HG action.
|
shows that HG activates JNK in cultured macrophages. To explore whether the JNK pathway is involved in HG action on IL-12, we tested the effect of the specific JNK inhibitor, JNKI-1, a peptide that competitively blocks the interaction between JNK and c-Jun. After depletion, macrophages were pretreated with fresh RPMI 1640 medium containing 10 µmol/liter JNKI-1 or 10 µmol/liter control peptide for 30 min, and MPMs were then treated with HG or NG for 3 h. Figure 5B shows that JNKI-1 significantly inhibited HG-induced IL-12 gene expression, whereas the JNKI control peptide had no effect. Neither the JNKI nor the JNKI control peptide had an effect on IL-12 mRNA expression under NG conditions. These data suggest that the JNK pathway is involved in HG-induced IL-12 mRNA expression.
|
B is also central to glucose-induced complications and oxidative stress. Because the IKK complex appears to be critical for NFB activation, IKK was used as an indicator of NFB activation. Figure 6A shows that HG time-dependently activated IKK activity. To explore the role of the NFB pathway in our model, we tested whether an NFB inhibitor could attenuate HG effects on IL-12 gene expression. After serum depletion, macrophages were pretreated with fresh RPMI 1640 medium containing 75 µg/ml of a specific NFB inhibitor or 75 µg/ml control NFB inhibitor (inactive control for NFB inhibitor) for 30 min. MPMs were then treated with HG or NG for 3 h. Figure 6B shows that the active NFB inhibitor completely blocked HG-induced IL-12 gene expression, whereas the NFB inhibitor control had no effect. Neither the NFB inhibitor nor the NFB control compound altered IL-12 mRNA expression under NG conditions. These data suggest that the NFB pathway is implicated HG action on IL-12 mRNA expression.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
. Taking IL-12 as an example, we have demonstrated that the HG-induced increase of mRNA expression was not elicited by high osmotic pressure because 25 mmol/liter concentration of D-glucose + mannitol or of D-glucose + 3OMG did not change the mRNA expression of IL-12. We also demonstrate that HG induced an increase in IL-12 protein secretion from macrophages. This is the first observation showing that HG activates mRNA expression of multiple cytokines in primary cultured MPMs. We further demonstrate that hyperglycemia increases the mRNA expression of multiple cytokine genes in macrophages isolated from STZ-induced diabetic mice as well as type 2 diabetic db/db mice, showing that the stimulatory effects of hyperglycemia on cytokine gene expression exists in vivo and suggesting that glucose independent of autoimmunity can activate these important cytokines. Activation of IL-12 and downstream transcription factors have been linked to atherosclerosis in mouse models and humans (6, 7, 8). Therefore, IL-12 was taken as an example to further investigate the regulatory mechanism of HG stimulation on cytokine mRNA expression.
It has been well established that increasing extracellular glucose concentration from 5.6 to 22.2 mmol/liter appears sufficient to accomplish an activation of diacylglycerol (DAG) and PKC (13). DAG-PKC activation has been considered an independent biochemical pathway involved in the pathogenesis of diabetic complications and is involved in the regulation of various cell functions including cytokine actions (14). There was a report showing an involvement of PKC in HG-induced MCP-1 in human peritoneal mesothelial cells (15). Interestingly, MCP-1 is one of the target genes produced by downstream transcription factor activation by IL-12. We first demonstrated that HG activated PKC activity by detecting an increase in the amount of phospho-PKC (pan) at Thr514 using specific anti-pan Thr51 antibody. It can be seen that HG time-dependently increases the density of pan. MARCKS protein is a widely accepted indicator of PKC activation. The level of phosphorylated MARCKS is generally believed to reflect PKC activation. Our data clearly illustrated that HG increases the density of phosphorylated MARCKS protein and the increase of the density of phosphor-MARCK protein has a same time pattern with that of the density changes of pan protein, strongly indicating that HG activates PKC activity in primary cultured macrophages. To investigate the possible involvement of PKC in HG-induced increases in IL-12 mRNA expression, two specific and structurally distinct PKC inhibitors, GF 109230X and calphostin C, were used. Both inhibitors completely blocked HG-induced IL-12 mRNA expression, strongly suggesting a role of DAG-PKC activation in HG-induced IL-12 mRNA expression. The PKC family includes at least 11 isoforms. There are reports showing that macrophages from various tissues express multiple types of PKC isoforms including , ß1 and 2, , 
, 
, and 
. However, it has been hypothesized that macrophage expression/function of PKC isoforms is tissue specific (alveolar vs. peritoneal) (16). Further studies will be necessary to elucidate the types of PKC isoforms that MPMs express and which isoform(s) of PKC mediate HG-induced IL-12 mRNA expression in murine peritoneal macrophages.
There is increasing evidence demonstrating a critical role of MAPK activation in the inflammatory response of macrophages (17). Evidence also shows that MAPK phosphatase-1, which dephosphorylates and inactivates these MAPKs, plays an important role in cytokine production induced by agonists. Stimulation of primary macrophages isolated from MAPK phosphatase-1-deficient mice by lipopolysaccharide resulted in a prolonged p38 MAPK phosphorylationand more robust and rapid TNF production, compared with wild-type macrophages (18). In the present study, we not only demonstrated that HG activated p38 activity in macrophages, which is consistent with other reports, but also a p38 MAPK inhibitor, SB202190, significantly reduced HG-induced IL-12 mRNA expression, suggesting an involvement of the p38 MAPK pathway. Our data are consistent with the data in a report showing that the inhibition of the phosphorylation of p38 MAPK is concomitant with a down-regulation of IL-12 p40 production (19).
JNK is an inflammation-related MAPK (20). In the present study, we used JNKI-1 as a relatively specific inhibitor for JNK-1, JNK-2, and JNK-3. JNKI-1 works by inhibiting the interaction between JNK and its substrate (21). JNKI-1 almost completely suppressed HG-induced IL-12 mRNA expression without effect on basal IL-12 mRNA expression. In contrast, the JNK inhibitor 1 control peptide, an inactive analog of JNKI-1, did not block HG-induced IL-12 mRNA expression, further supporting the conclusion that JNKI-1 specifically inhibited and JNK mediated HG-induced IL-12 mRNA expression.
JNK has been directly linked to NFB regulation (22). Furthermore, evidence shows that IL-12 is an inducible, heterodimeric, disulfide-linked cytokine composed of p35 and p40 subunits. Expression of the p35 subunit is constitutive and ubiquitous (23), whereas the biological activity of IL-12 is regulated mainly by the induction of p40, which reported to be regulated primarily at the level of transcription including NFB (24). For NFB activation, phosphorylation of IKK appears to be critical. Therefore, we chose the phosphorylation of IKK as an indicator of NFB activation. Our data clearly show an increase in the amount of phosphorylated IKK in HG conditions vs. NG condition, demonstrating an stimulatory effect of HG on NFB activation. NFB inhibitor, which contains the nuclear localization sequence residues 360–369 of NFB p50 and inhibits translocation of the NFB active complex into the nucleus (25), was used for evaluating whether NFB is involved in the regulation of HG-induced IL-12 mRNA expression. Our results demonstrate that blockade of the NFB translocation completely suppresses HG-induced IL-12 mRNA expression, strongly suggesting an involvement of NFB in the action of glucose.
We have not pursued in this study whether there is a signaling linearity connecting PKC, p38 MAPK, JNK, and NFB. Data have shown that pretreatment of neutrophils with the structurally distinct PKC/ß inhibitors Go6976 or GF109203X decreased nuclear translocation of NFB and production of the proinflammatory cytokine TNF. These inhibitors also prevented lipopolysaccharide-induced phosphorylation of IKK/ß, phosphorylation and degradation of IB-, and phosphorylation of the 65 subunit of NFB. Activation of p38 and JNK also was diminished in neutrophils in which PKC/ß was inhibited (26). These data clearly suggest a cascade involving PKC to MAPK to NFB to cytokine production in neutrophils. The signal transduction linking PKC, MAPK, and NFB in HG-induced IL-12 mRNA expression will require further investigation. However, elegant studies have shown that a role for mitochondrial-induced oxidative stress as a common pathway leading to glucose-induced complications (14). It will be interesting in future studies to explore the role of the mitochondria in glucose-induced IL-12 production in macrophages. Our studies also are supported by a recent report (27) showing a key role of oxidative stress in generating IL-12 in mouse peritoneal macrophages.
Summary
In the present study, HG induced an increase in multiple proinflammatory cytokines in MPMs, in vitro and in two diabetic mouse models. This increase induced by HG was not due to osmotic pressure, suggesting that this is a specific effect by high glucose. IL-12 has been taken as an example, and our data show that PKC, p38 MAPK, JNK, and NFB are involved in the regulation of HG-induced IL-12 gene expression. These results suggest that glucose-induced macrophage generation of proinflammatory could be involved in both short-term and long-term vascular complication of diabetes.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
The authors have nothing to declare.
First Published Online February 2, 2006
Abbreviations: DAG, Diacylglycerol; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HG, high glucose; IKK, inhibitory-B kinase; JNK, c-jun-N-terminal kinase; MCP, monocyte chemoattractant protein; MPM, mouse peritoneal macrophage; NFB, nuclear factor-B; NG, normal glucose; 3OMG, 3-O-methyl-glucose; p38, p38 MAPK; pan, phosphor-PKC; PKC, protein kinase C; STZ, streptozotocin.
Received April 29, 2005.
Accepted for publication January 23, 2006.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-deficient nonobese diabetic mice, revealing pathogenic and protective effects of IL-12-induced IFN-. J Immunol 170:5491–5501CT method. Methods 25:402–408[CrossRef][Medline] and IL-1ß production. Shock 9:256–260[Medline]B pathways for the expression of proinflammatory cytokines and nitric oxide. J Biol Chem 280:8617–8627B and MAPK pathways and in the regulation of cell proliferation and apoptosis. Cell Signal 14:123–131[CrossRef][Medline]B half-site. Mol Cell Biol 15:5258–5267[Abstract] in monocytic cells. J Exp Med 183:147–157B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence. J Biol Chem 270:14255–14258/ß in TLR4 and TLR2-dependent activation of NF-B. Cell Signal 17:385–394[CrossRef][Medline]This article has been cited by other articles:
 |
|
 |
|
  H. K. Takahashi, S. Mori, H. Wake, K. Liu, T. Yoshino, K. Ohashi, N. Tanaka, K. Shikata, H. Makino, and M. Nishibori Advanced Glycation End Products Subspecies-Selectively Induce Adhesion Molecule Expression and Cytokine Production in Human Peripheral Blood Mononuclear Cells J. Pharmacol. Exp. Ther., July 1, 2009; 330(1): 89 - 98. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.- J. Peng, J. Nanduri, G. Yuan, N. Wang, E. Deneris, S. Pendyala, V. Natarajan, G. K. Kumar, and N. R. Prabhakar NADPH Oxidase Is Required for the Sensory Plasticity of the Carotid Body by Chronic Intermittent Hypoxia J. Neurosci., April 15, 2009; 29(15): 4903 - 4910. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Nacci, M. Tarquinio, L. De Benedictis, A. Mauro, A. Zigrino, M. R. Carratu, M. J. Quon, and M. Montagnani Endothelial Dysfunction in Mice with Streptozotocin-induced Type 1 Diabetes Is Opposed by Compensatory Overexpression of Cyclooxygenase-2 in the Vasculature Endocrinology, February 1, 2009; 150(2): 849 - 861. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Johansson, F. Kramer, S. Barnhart, J. E. Kanter, T. Vaisar, R. D. Merrill, L. Geng, K. Oka, L. Chan, A. Chait, et al. Type 1 diabetes promotes disruption of advanced atherosclerotic lesions in LDL receptor-deficient mice PNAS, February 12, 2008; 105(6): 2082 - 2087. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. Aroeira, A. Aguilera, J. A. Sanchez-Tomero, M. A. Bajo, G. del Peso, J. A. Jimenez-Heffernan, R. Selgas, and M. Lopez-Cabrera Epithelial to Mesenchymal Transition and Peritoneal Membrane Failure in Peritoneal Dialysis Patients: Pathologic Significance and Potential Therapeutic Interventions J. Am. Soc. Nephrol., July 1, 2007; 18(7): 2004 - 2013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Kanter, F. Johansson, R. C. LeBoeuf, and K. E. Bornfeldt Do Glucose and Lipids Exert Independent Effects on Atherosclerotic Lesion Initiation or Progression to Advanced Plaques? Circ. Res., March 30, 2007; 100(6): 769 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Sherry, J. C. O'Connor, J. M. Kramer, and G. G. Freund Augmented Lipopolysaccharide-Induced TNF-{alpha} Production by Peritoneal Macrophages in Type 2 Diabetic Mice Is Dependent on Elevated Glucose and Requires p38 MAPK J. Immunol., January 15, 2007; 178(2): 663 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. X. Chen, D. Duan, K. D. O'Neill, and S. M. Moe High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells Nephrol. Dial. Transplant., December 1, 2006; 21(12): 3435 - 3442. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-J. Peng, G. Yuan, F. J. Jacono, G. K. Kumar, and N. R. Prabhakar 5-HT evokes sensory long-term facilitation of rodent carotid body via activation of NADPH oxidase J. Physiol., October 1, 2006; 576(1): 289 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-l. Li, M. A. Reddy, Q. Cai, L. Meng, H. Yuan, L. Lanting, and R. Natarajan Enhanced Proatherogenic Responses in Macrophages and Vascular Smooth Muscle Cells Derived From Diabetic db/db Mice Diabetes, September 1, 2006; 55(9): 2611 - 2619. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
