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Am J Physiol Heart Circ Physiol 292: H1694-H1699, 2007. First published November 17, 2006; doi:10.1152/ajpheart.01063.2006
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TRANSLATIONAL PHYSIOLOGY

Deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1beta

Meijing Wang,1 Troy Markel,1,* Paul Crisostomo,2,* Christine Herring,1 Kirstan K. Meldrum,1 Keith D. Lillemoe,1 and Daniel R. Meldrum1,2,3

Departments of 1Surgery, 2Cellular and Integrative Physiology, and 3Immunology, Indiana University School of Medicine, Indianapolis, Indiana

Submitted 27 September 2006 ; accepted in final form 16 November 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Tumor necrosis factor-{alpha} (TNF-{alpha}) plays an important role in the development of heart failure. There is a direct correlation between myocardial function and myocardial TNF levels in humans. TNF may induce local inflammation to exert tissue injury. On the other hand, suppressors of cytokine signaling (SOCS) proteins have been shown to inhibit proinflammatory signaling. However, it is unknown whether TNF mediates myocardial inflammation via STAT3/SOCS3 signaling in the heart and, if so, whether this effect is through the type 1 55-kDa TNF receptor (TNFR1). We hypothesized that TNFR1 deficiency protects myocardial function and decreases myocardial IL-6 production via the STAT3/SOCS3 pathway in response to TNF. Isolated male mouse hearts (n = 4/group) from wild-type (WT) and TNFR1 knockout (TNFR1KO) were subjected to direct TNF infusion (500 pg·ml–1·min–1 x 30 min) while left ventricular developed pressure and maximal positive and negative values of the first derivative of pressure were continuously recorded. Heart tissue was analyzed for active forms of STAT3, p38, SOCS3 and SOCS1 (Western blot analysis), as well as IL-1beta and IL-6 (ELISA). Coronary effluent was analyzed for lactate dehydrogenase (LDH) activity. As a result, TNFR1KO had significantly better myocardial function, less myocardial LDH release, and greater expression of SOCS3 (percentage of SOCS3/GAPDH: 45 ± 4.5% vs. WT 22 ± 6.5%) after TNF infusion. TNFR1 deficiency decreased STAT3 activation (percentage of phospho-STAT3/STAT3: 29 ± 6.4% vs. WT 45 ± 8.8%). IL-6 was decreased in TNFR1KO (150.2 ± 3.65 pg/mg protein) versus WT (211.4 ± 26.08) mice. TNFR1 deficiency did not change expression of p38 and IL-1beta following TNF infusion. These results suggest that deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1beta.

ischemia; reperfusion; inflammation; cytokines; signaling; tumor necrosis factor receptor type 1; suppressors of cytokine signaling

TUMOR NECROSIS factor-{alpha} (TNF-{alpha}) is a proinflammatory cytokine that plays a role in cellular differentiation, apoptosis, and inflammation (23, 28). TNF can be produced locally from different cells, including cardiac myocytes, smooth muscle cells, and endothelial cells in response to endotoxemia, ischemia, and trauma (23, 24, 31). Locally produced TNF contributes to depression of myocardial contractile function, induction of cardiomyocyte apoptosis, as well as induction of proinflammatory signaling (8, 15, 18). TNF exhibits its biological effect through two distinct surface receptors, TNFR1 (p55) and TNFR2 (p75). Both receptors have been observed in many cell types, including cardiac myocytes (34). Although most animal studies clearly showed that TNF exerts detrimental effects following experimental ischemia-reperfusion (I/R) (6, 20, 22, 25), clinical trials indicated that anti-TNF therapy was associated with increased mortality (7). This led to the important appreciation that the regulatory balance of TNF signaling likely depends on different TNF receptor-induced pathways with different cellular fates (cell survival vs. apoptosis).

TNFR1 initiates the majority of TNF effects in most cell types, including the heart. It has been reported that through TNFR1, TNF exerts negative inotropic effects on the myocardial contractile function (26) and induces cardiac myocyte apoptosis (15). Recent evidence demonstrated significant improvement in myocardial function in TNFR1 knockout (TNFR1KO) mice compared with wild-type (WT) mice after myocardial infarction (27, 39). Although most studies have focused on TNFR1-induced myocardial dysfunction by calcium dyshomeostasis (45), nitric oxide production (32), and apoptosis, little information exists in TNFR1-induced myocardial inflammation. Indeed, TNF plays an important role in the execution of an immune response.

Recently, suppressors of cytokine signaling (SOCS) proteins have been reported to inhibit proinflammatory/proapoptotic signaling in the heart (1). They do so by inhibiting intracellular signaling pathways activated by proinflammatory cytokines. However, it is unknown whether TNF mediates myocardial inflammation via STAT3/SOCS3 signaling in the heart and, if so, whether this effect is through the type 1 55-kDa TNFR1.

Therefore, we hypothesized that TNFR1 deficiency would protect myocardial function and decrease myocardial inflammation via the STAT3/SOCS3 pathway in response to TNF. The purpose of this study was to determine the effect of TNFR1 on myocardial function and myocardial inflammatory pathways by using mice with a targeted deletion of TNFR1.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. WT and TNFR1KO mice (Jackson, Bar Harbor, ME) were fed a standard diet and acclimated in a quiet quarantine room for 2 mo before the experiments. The animal protocol was reviewed and approved by the Indiana Animal Care and Use Committee of Indiana University. All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health (NIH Publication No. 85-23, Revised 1996).

A total of eight isolated mouse hearts (n = 4/group) were subjected to the same protocol with TNF infusion (500 pg·ml–1·min–1) for 30 min after 15 min of equilibration. Additional three isolated mouse hearts were performed as control without TNF infusion.

Isolated heart preparation (Langendorff) and measurement of cardiac function. Experiments were performed with the use of a Langendorff apparatus as described previously (39) for use in mouse heart. Briefly, mice were anesthetized (pentobarbital sodium, 60 mg/kg ip) and heparinized (500 units ip), and hearts were rapidly excised via median sternotomy and placed in 4°C Krebs-Henseleit solution. The aorta was cannulated, and the heart was perfused with oxygenated (95% O2-5% CO2) Krebs-Henseleit solution (37°C). Coronary flow was measured by collecting pulmonary artery effluent. Data were continuously recorded by using a PowerLab 8 preamplifier/digitizer (AD Instruments, Milford, MA) and an Apple G4 PowerPC computer (Apple Computer, Cupertino, CA). The maximal positive and negative values of the first derivative of pressure (±dP/dt) were calculated using PowerLab software.

Lactate dehydrogenase assay. Lactate dehydrogenase (LDH) is released from damaged cells, and the measurement of LDH activity indicates the severity of cell death and cell lysis. Coronary effluent was collected and stored at –80°C freezer until enzymatic analysis for LDH activity by using a commercially available kit (Cytotoxicity Detection Kit-LDH, Roche Diagnostics, Indianapolis, IN).

Myocardial IL-1beta and IL-6. Myocardial IL-1beta and IL-6 were determined by ELISA using a commercially available ELISA set (R&D Systems, Minneapolis, MN). ELISA was performed according to the manufacturer's instructions. All samples and standards were measured in duplicate.

Western blot analysis. Western blot analysis was performed to measure p38 MAPK, STAT3, SOCS3, and SOCS1 proteins. Heart tissue was homogenized in cold buffer containing 20 mM Tris (pH 7.5), 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 2.5 mM sodium pyrophosphate, 1 mM beta-glycerophosphate, 1 mM Na3VO4, 1 µg/ml leupeptin, and 1 mM PMSF and then centrifuged at 12,000 rpm for 5 min. The protein extracts (30 µg/lane) were subjected to electrophoresis on a 12% Tris·HCl gel from Bio-Rad and transferred to a nitrocellulose membrane, which was stained by Naphthol Blue-Black to confirm equal protein loading. The membranes were incubated in 5% dry milk for 1 h and then incubated with the following primary antibodies: p38 MAPK antibody, phospho-p38 MAPK (Thr180/Tyr182), STAT3 antibody, phospho-STAT3 antibody (Cell Signaling Technology, Beverly, MA), SOCS3, and SOCS1 antibodies (Santa Cruz Biotechnology, Santa Cruz, CA). The membranes were then incubated with horseradish peroxidase-conjugated goat anti-rabbit IgG secondary antibody and detection using SuperSignal West Pico stable peroxide solution (Pierce, Rockford, IL). Films were scanned by using an Epson Perfection 3200 Scanner (Epson America, Long Beach, CA), and band density was analyzed by using ImageJ software (NIH).

Presentation of data and statistical analysis. All reported values are means ± SE (n = 4/group). Data were compared by using two-way ANOVA with post hoc Bonferroni test or Student's t-test. A two-tailed probability value of <0.05 was considered statistically significant.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
TNF-decreased myocardial function dependent on TNFR1. TNF infusion resulted in a progressive decrease in myocardial function. During the 10-min equilibration period, hearts maintained stable left ventricular developed pressure and ±dP/dt, which were significantly depressed by 30 min of TNF infusion in WT hearts (Fig. 1). However, TNFR1KO resulted in improved myocardial function compared with WT (left ventricular developed pressure: 37.9 ± 4.4 vs. WT 20.6 ± 3.2 mmHg; +dP/dt: 1176.4 ± 159.1 vs. WT 589.1 ± 85.6 mmHg/s; –dP/dt: –877.2 ± 115.4 vs. WT –448.6 ± 61.8 mmHg/s) with exposure to equivalent amounts of TNF.


Figure 1
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  		Fig. 1. Myocardial contractile function following TNF (500 pg·ml–1·min–1) infusion in age-matched wild-type (WT) and TNF recptor 1 (TNFR1) knockout (TNFR1KO) mouse hearts perfused with modified Krebs-Henseleit solution. TNF infusion resulted in a progressive decline in myocardial function in WT hearts, which was improved in TNFR1KO hearts. A: left ventricular developed pressure (LVDP). B and C: maximum positive (+dP/dt; B) and negative (–dP/dt; C) first derivative of pressure. Results are means ± SE and are represented as percentage of equilibration (Eq). *P < 0.05 vs. WT; #P < 0.05 vs. Eq.

 
Effect of TNFR1 on cardiomyocyte damage in response to TNF. Following TNF infusion, increased LDH release in coronary effluent was observed. Interestingly, TNFR1 deficiency resulted in less LDH release compared with that in WT hearts (Fig. 2).


Figure 2
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  		Fig. 2. Lactate dehydrogenase (LDH) release in coronary effluent following TNF infusion. Shown value is Eq, 10 min, 20 min, and 30 min of TNF infusion, respectively. Results are means + SE. *P < 0.05 vs. Eq; #P < 0.05 vs. WT.

 
Effect of TNFR1 on expression of TNF-induced myocardial IL-1beta and IL-6. TNF infusion resulted in significantly more production of myocardial IL-1beta (751 ± 18 vs. control 362 ± 7 pg/mg protein) and IL-6 (211.4 ± 26 vs. control 74.5 ± 17 pg/mg protein) (Fig. 3). TNFR1 deficiency did not change TNF-induced IL-1beta expression. However, TNF-induced IL-6 production (150 ± 3.7 vs. WT 211.4 ± 26 pg/mg protein) was markedly decreased by TNFR1KO.


Figure 3
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  		Fig. 3. Production of myocardial IL-6 (A) and IL-1beta (B) after TNF infusion was assessed by ELISA. TNF induced significantly more IL-6 and IL-1beta compared with those in control. TNFR1 deficiency resulted in less production of myocardial IL-6 but not IL-1beta. (means ± SE, n = 3 to 4 hearts/group. *P < 0.05 vs. control, #P < 0.05 vs. WT).

 
TNF induced myocardial p38 MAPK activation. The myocardial phosphorylated/active p38 and nonphosphorylated/total p38 MAPK were assessed by Western blot analysis (Fig. 4). More phosphorylated p38 MAPK (percentage of phosphorylated p38/total p38: 29 ± 14.6% vs. control 11.3 ± 0.4%) was observed in the heart exposed to TNF. This result indicated that TNF induced significantly more activation of p38 MAPK. However, there was no significant difference in the ratio of phospho-p38 to p38 MAPK between WT and TNFR1KO following TNF infusion.


Figure 4
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  		Fig. 4. Top: expression of activated p38 MAPK and total p38 MAPK was measured by Western blot analysis. TNF infusion resulted in more activation of myocardial p38 MAPK, which was independent of TNFR1. Densitometry data of phospho (p)-p38 MAPK (% of total p38 MAPK) are shown (means ± SE, n = 3 to 4 hearts/group). Bottom: representative immunoblots (2 lanes/group).

 
Effect of TNFR1 on TNF-induced expression of SOCS3 and activation of STAT3. Following TNF infusion, expression of SOCS3 protein (percentage of SOCS3/GAPDH: 45 ± 4.5% vs. WT 22 ± 6.5%) was found to be higher in TNFR1KO hearts compared with WT hearts (Fig. 5A). Moreover, TNFR1 deficiency resulted in less activation of STAT3 following TNF infusion (Fig. 5B). Although no significant difference in myocardial SOCS1 expression was noted in response to TNF infusion, the trend of higher SOCS1 level was observed in TNFR1KO hearts (Fig. 5C).


Figure 5
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  		Fig. 5. Expression of myocardial suppressors of cytokine signaling 3 (SOCS3; A), activation of STAT3 (B), and SOCS1 protein level (C) after TNF infusion were measured by Western blot analysis. More expression of myocardial SOCS3 existed in TNFR1KO hearts compared with WT hearts following TNF infusion. Shown are densitometry data of SOCS3, SOCS1 (% of GAPDH), and p-STAT3 (% of STAT3) (means ± SE, n = 3 to 4 hearts/group, *P < 0.05 vs. WT) and representative immunoblots (2 lanes/group).

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In the present study, we clearly demonstrated that 1) TNF induced myocardial contractile dysfunction through TNFR1, which was associated with less LDH release in TNFR1KO hearts, and 2) deficiency of TNFR1 limits acute myocardial inflammation through SOCS3 and IL-6.

Cardiac myocytes themselves produce substantial amounts of TNF in response to endotoxemia, I/R, and trauma (23, 24, 31), which then lead to myocardial dysfunction. It is well documented that myocardial TNF is increased in acute myocardial ischemia (12, 24). Our previous studies have shown that I/R-induced myocardial dysfunction was associated with an increase of myocardial TNF production (37, 38). Here, once again, we indicated that TNF infusion into the heart depressed myocardial contractile function. The hemodynamic effects of TNF are characterized by decreased myocardial contractile efficiency and reduced ejection fraction, hypotension, decreased systemic vascular resistance, and biventricular dilatation (23). TNF has been shown to exert a negative inotropic effect via the disruption of calcium homeostasis (45) and increased production of nitric oxide (41, 42, 44). Although both of TNFR1 and TNFR2 are present on the cardiac myocyte membrane, the majority effect of TNF is initiated by TNFR1. It has been reported that TNF disrupted cardiac excitation-contraction coupling through TNFR1-mediated inhibition of L-type calcium channel-induced calcium influx (23). In addition, stress-induced second messenger sphingolipid metabolites have been shown to participate in intracellular signal transduction following TNF binding to the TNFR1. Blockade of sphingosine production abolished TNF-induced contractile dysfunction (26).

TNF has been reported to also induce apoptosis in many cell types, including the myocardium. TNF binding to TNFR1 or Fas resulted in activation of procaspase-8. Caspase-8 then activates downstream caspase-3 and induces the classic extrinsic death pathway (11, 21, 36), which is also responsible for TNF-induced contractile dysfunction in a prolonged myocardial injury (39a). However, some scientists concluded that TNF-induced cardiac myocyte apoptosis does not happen in the presence of TNF by itself in vivo (17, 19). Therefore, given that our experimental period (only 30 min of TNF infusion) was too brief to observe significant apoptosis, we did not perform apoptotic-related assays in this experimental model. However, the present study indicated that increased myocardial LDH release existed following TNF infusion. In addition, TNFR1 ablation resulted in less LDH release in the myocardial response to TNF. It suggests that there were less damaged cells in TNFR1KO mice, which was correlated with improved myocardial function in TNFR1KO hearts subjected to TNF exposure.

In addition, TNF is able to induce other inflammatory cytokine synthesis. It has been reported that TNF is an upstream initiator of the reperfusion-dependent cytokine release in experimental canine myocardial I/R (8). Cardiac-specific overexpression of TNF has been shown to elevate myocardial IL-1beta and matrix metalloproteinase-1 levels in the murine model (16). Using TNF receptor fusion protein has decreased LPS-induced IL-1beta in animal experiments (14). Our previous study demonstrated that TNF might mediate production of myocardial IL-beta and IL-6 via p38 MAPK in response to endotoxemia (38, 40). p38 MAPK is an important mediator in cellular inflammatory response (29, 30, 33). Indeed, it has been demonstrated that p38 MAPK regulates TNF-induced production of IL-1beta and IL-6 in murine embryo fibroblasts (43). Moreover, TNF-induced IL-6 production is mediated by p38 MAPK, and this process occurs at the transcriptional level (3, 35). In parallel, the present study demonstrates that direct infusion of TNF into the heart resulted in increased production of IL-1beta and IL-6, which is in line with elevated activation of myocardial p38 MAPK in response to TNF. Interestingly though, only TNF-induced IL-6 levels were decreased in TNFR1KO hearts. The mechanism involved in TNFR1-mediated IL-6 production in the heart, therefore, remains unclear.

Recently, SOCS proteins have been reported to inhibit proinflammatory/proapoptotic signaling in the heart (1). SOCS proteins may be induced by various stimuli (1) and participate in the important process of controlling proinflammatory signals. They do so by inhibiting intracellular signaling pathways activated by proinflammatory cytokines. It has been demonstrated that TNF induces expression of SOCS3 in the liver (10), rat liver macrophage, and mouse macrophage (4). In the present study, we indicated that expression of SOCS3 existed in TNF-exposed heart tissue. To date, no data show the exact mechanisms of TNF-mediated SOCS3 expression and what receptor(s) is involved in this process. Herein we found that a deficiency of TNFR1 increased myocardial SOCS3 protein expression, which is in line with our previous result of an I/R-induced increased expression of SOCS3 that is increased in TNFR1KO hearts (39). These data suggest that SOCS3 expression may be attributed to TNFR2 signaling. However, the detailed mechanisms need further investigation. In addition, although the trend of higher level in myocardial SOCS1 expression was noted in the TNFR1KO hearts subjected to TNF, there was no significant difference in SOCS1 protein level between WT and TNFR1KO mice.

SOCS3, in turn, have an inhibitory effect on inflammatory cytokine signaling and myocardial dysfunction (5). It has been demonstrated that recombinant cell-penetrating forms of SOCS3 protect animals from the lethal effects of bacteria and endotoxemia by suppressing inflammation (13). TNF has been shown to inhibit IL-6 signaling (STAT3 pathway) via SOCS3 in macrophage (4). Therefore, it is not surprising that in this study, increased SOCS3 expression decreased IL-6 production and activation of myocardial STAT3 in TNFR1KO hearts exposed to TNF. However, SOCS3 did not affect TNF-induced myocardial IL-1beta levels in TNFR1-deficient mice. SOCS3 appears to mediate IL-1beta signaling through IL-1 receptor antagonist (2). Therefore, a potential explanation for our data is that TNF-induced SOCS3 expression may induce IL-1 receptor antagonist to bind IL-1beta, subsequently inhibiting IL-1 signaling without decreasing IL-1beta production in TNFR1KO heart.

In summary, these results suggest that TNFR1 plays an important role in myocardial dysfunction. There are complex interactions between signaling proteins, such as p38 MAPK and SOCS3, in TNFR1-mediated effects. Further investigation in this area may yield a more complete understanding of TNF signaling in hopes of advancing ischemic heart injury treatments that target specific receptor actions.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported in part by National Institute of General Medical Sciences Grant R01-GM-070628 (to D. R. Meldrum), American Heart Association Postdoctoral Fellowship 0526008Z (to M. Wang), and National Research Service Award F32-HL-085982. This investigation was conducted in a facility constructed with support from Division of Research Resources Research Facilities Improvement Program Grant C06-RR-015481-01.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. R. Meldrum, 545 Barnhill Dr., Emerson Hall 215, Indianapolis, IN 46202 (e-mail: dmeldrum{at}iupui.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

* T. Markel and P. Crisostomo contributed equally to this work. Back


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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