Inhibition of inflammation by SP600125 in cholestatic liver injury is dependent on the administration‑based exposure profile
- Authors:
- Published online on: September 29, 2020 https://doi.org/10.3892/ijmm.2020.4742
- Pages: 2271-2279
Abstract
Introduction
c-Jun-N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) family and includes 3 isoforms in mammals, namely JNK1, JNK2 and JNK3 (1). JNK1 and JNK2 are expressed in almost all cells, whereas JNK3 is mainly expressed in the brain, heart, and testis (2). The JNK pathway may be activated by cytokines, pathogens, toxins, drugs and metabolic changes (3). JNK activation is involved in cell death, differentiation, proliferation, and tumorigenesis in hepatocytes (4). In hepatic macrophages and hepatic stellate cells, JNK was revealed to contribute to liver inflammation and fibrosis (5). The JNK pathway also regulates inflammation, and insulin resistance, which are associated with hepatic diseases such as non-alcoholic steatosis, fibrosis, and hepatocellular carcinoma (3).
SP600125 is widely used in biochemical studies as a selective JNK inhibitor (6) and it can block the activation of JNK to modulate the expression of inflammatory factors (6-8). Additionally, this inhibitor has been used in numerous cellular models to investigate the underlying pathophysiological and pharmacological mechanisms. Incubation with bile acid significantly reduced L02 cell viability, and this effect was reduced by pre-treatment with 20 µM SP600125, which involved downregulation of IL-1β and inhibition of JNK phosphorylation (9). In MC3T3-E1 cells, 25 and 50 µM SP600125 reduced osteoblast apoptosis in an LPS-induced model and restored differentiation of osteoblasts (10).
In a rat model, administration of 30 mg/kg SP600125 by intraperitoneal (i.p.) injection once per day for 8 weeks suppressed autophagy and attenuated insulin resistance by inhibiting JNK signalling (11). In C57BL/6 mice, a single dose of 10 and 30 mg/kg SP600125 by i.p. injection inhibited 3-chloro-1,2-propanediol esters-induced apoptosis by downregulating the JNK/p53 pathway in tubular cells (12). In a type 1 diabetic mouse model induced by streptozocin, 5 mg/kg SP600125 by intragastric (i.g.) injection every other day for 3 months inhibited cardiac fibrosis, oxidative stress, endoplasmic reticulum stress, and cell death by inhibiting the JNK pathway (13,14). However, the optimal administration regimen of SP600125 inhibiting the JNK pathway and its exposure profile have yet to be determined.
Cholestasis is caused by disrupted structure and impaired function of the hepatobiliary system, which occurs in a number of clinical disorders (15). Patients with cholestasis may even-tually develop sepsis, immune depression, cardiovascular, hepatic and renal failure (16). Cholestatic liver injury is closely associated with several inflammatory pathways (17,18). It was reported that the synthesis and excretion of bile acids increased the levels of TNF-α and IL-1β in hepatic Kupffer cells (19). In addition, cytokines, cholic acid and deoxycholic acid have been revealed to activate the JNK/c-Jun pathway (20,21). In cellular models, the JNK pathway was also found to regulate bile acid metabolism (22,23). Thus, α-naphthylisothiocyanate (ANIT)-induced cholestatsis is a suitable model for investigating the inhibitory effect of SP600125 on the JNK pathway.
In the present study, ANIT-induced cholestatic liver injury was used to evaluate the inhibitory effect of SP600125 administered by i.p. and i.g. injections, on the JNK pathway. The data were revealed to be informative in designing biomedical experiments where SP600125 may be used.
Materials and methods
Chemicals and reagents
ANIT was purchased from Sigma-Aldrich; Merck KGaA. Alkaline phosphatase (ALP), total bile acid (TBA), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) assay kits were purchased from Ningbo Ruiyuan Biotechnology Co., Ltd. TRIzol® and the reverse transcription kit were purchased from Invitrogen (Thermo Fisher Scientific, Inc). The LightCycle 480 SYBR Green I Master Mix was obtained from Roche Diagnostics. Antibodies against phosphorylated (p)-MAPK kinase 4 (MKK4) (1:1,000; product no. 4514) and total (t)-MKK4 (1:1,000; product no. 9152), t-JNK (1:1,000; product no. 9252) and p-JNK (1:1,000; product no. 9912), p-c-Jun (1:1,000; product no. 2361) and t-c-Jun (1:1,000; product no. 9165), were obtained from Cell Signalling Technology, Inc. Primary antibodies against CYP7A1 (1:1,000; product code ab65596), CYP8B1(1:1,000; product code ab191910), GAPDH (1:10,000; product code ab181602) were acquired from Abcam. Secondary antibody IgG H&L (HRP) was also obtained from Abcam (1:2,000; product code ab205718). All the other chemicals were of the highest grade available from commercial sources.
Animals and treatment
A total of 50 mice were maintained under a 12-h light/dark cycle with free access to water and a commercial diet. The SPF room housing the mouse cages was set at 23±1°C with a relative humidity of 60-70%. All the mice were allowed to acclimate for 7 days before the experiments. The procedures performed were approved by the Animal Care and Use Committee of Ningbo University. Twenty of the mice were assigned into 4 groups (n=5/group) as follows: Negative control (Con), ANIT/positive control (ANIT), ANIT/SP600125-i.p. (A-SP-i.p.) and ANIT/SP600125-i.g. (A-SP-i.g.). A single dose of 15 mg/kg SP600125 dissolved in corn oil was administered by i.p. or i.g. injections to pre-treat the mice. At 30 min after SP600125 administration, a single dose of 75 mg/kg ANIT in corn oil was injected to induce cholestasis. At 48 h after the treatment, the mice were weighed and then killed by asphyxiation after blood collection. To perform euthanasia, the mouse cage was moved into a trans-parent polycarbonate chamber. Compressed CO2 gas (purity >99%) was introduced at a rate of 30% chamber volume per min using a CO2-specific regulator. Death was confirmed by observing absence of respiratory movement and faded eye colour. The chamber was cleaned thoroughly to remove any potential risk for euthanasia. Liver tissues and the gallbladder were harvested for calculation of liver and gallbladder indices. Half of the isolated liver tissues were cut and fixed in 10% neutral buffered formalin at room temperature for 24 h. The remaining liver tissues were immediately frozen and stored under at −80°C.
Biochemical analysis and histopathological assessment
The Multiskan GO (Thermo Fisher Scientific, Inc.) was used to measure the TBA, ALP, ALT and AST levels in the serum according to the manufacturer's instructions.
The liver tissues were dehydrated through serial concentrations of alcohol (70, 80, 90 and 100%) and xylene, followed by paraffin embedding at 60 C and cooled to −20 C. The paraffin block was cut into 4-µm sections which were then stained with hematoxylin for 3 min and eosin for 2 min at room temperature. A BX51 light microscope (Olympus Corporation) at ×40 and ×400 magnification and ten serial sections per preparation were used to randomly capture histopathological images.
Quantitative PCR (qPCR) and western blot (WB) analysis
Processing of liver samples for the qPCR and WB analysis followed previously published procedures with slight modifications (18). Specifically, a 5-µl PCR system was designed for the 384 plate. For qPCR analysis, the primers (Table SI) were also obtained from a public database (http://mouseprim-erdepot.nci.nih.gov). This system configuration followed the protocols provided by the manufacturer. Melting curves were used to assess primer specificity. 18S rRNA was used as an internal standard to calculate the relative transcription level for each run.
Concentration-time profile of SP600125
In a second pilot experiment, 30 mice were divided into 6 groups (n=5/group), as follows: SP600125-i.p.-A (SP-i.p.-A), SP600125-i.p.-B (SP-i.p.-B), SP600125-i.p.-C (SP-i.p.-C), SP600125-i.g.-A (SP-i.g.-A) SP600125-i.g.-B (SP-i.g.-B) and SP600125-i.g.-C (SP-i.g.-C). A single dose of 15 mg/kg SP600125 was administered by i.p. and i.g. injections. Blood (30 µl) was collected from the tail vein for exposure assessment. The blood collection was performed at 0.3, 1.5, 3, 6 and 14 h following SP600125 treatment in the SP-i.p.-A and SP-i.g.-A groups. Similarly, the blood collection in the SP-i.p.-B and SP-i.g.-B groups was performed at 0.5, 2, 8 and 18 h. For the SP-i.p.-C and SP-i.g.-C groups, blood was collected at 1, 4, 10 and 24 h after SP600125 treatment. The determination followed previously published procedures (18).
Statistical analysis
All data were expressed as the mean ± SD. GraphPad Prism (version 7.0; GraphPad Software, Inc.) for Windows was used for the data analysis. Two-samples t-test was used to test the difference between two groups, and Bonferroni's correction was performed for all P-values. The Cmax and AUC were calculated using Drug and Statistics (Version 3.0; Mathematical Pharmacology Professional Committee of China, Shanghai, China) (24).
Results
Cholestatic liver injury is differentially inhibited
The levels of the biochemical markers ALP, TBA, ALT and AST in the serum were all markedly increased in the ANIT group compared with those in the control group (Fig. 1; all P<0.0001). The serum TBA levels in the A-SP-i.p. and A-SP-i.g. groups were similar to those in the ANIT group (Fig. 1A). In the A-SP-i.p. group, but not in the A-SP-i.g. group, the ALP, ALT and AST levels in serum were decreased compared with those in the ANIT group (Fig. 1B-D; all P<0.0001). The hepatic pathological analysis in the control group revealed characteristic features (Fig. 2A). Loss of cellular boundaries, degenerative changes and marked necrosis were identified in the ANIT group (Fig. 2B). The A-SP-i.p. group, but not the A-SP-i.g. group, exhibited no significant difference compared with the control group (Fig. 2C and D). Thus, pre-treatment with SP600125 at a dose of 15 mg/kg by i.p. injection reversed the liver injury induced by ANIT in mice, although the serum TBA level did not improve. However, the aforementioned protective effect was not observed in the mice pre-treated with SP600125 at 15 mg/kg by i.g. injection.
Adaptation of bile acid metabolism and transport
The rate-limiting enzymes CYP7A1 and CYP8B1 play an important role in bile acid homeostasis (25). ANIT challenge decreased the CYP7A1 and CYP8B1 mRNA levels in the ANIT group compared with those in the control group (Fig. 3A and B; P<0.01 and P<0.001). In the A-SP-i.p. group, but not in the A-SP-i.g. group, both CYP7A1 and CYP8B1 mRNA levels were increased compared with those in the ANIT group (Fig. 3A and B; P<0.05 and P<0.01). In the A-SP-i.g. group, CYP7A1 and CYP8B1 mRNA levels were lower compared with those in the A-SP-i.p. group, as the adaptation remained strong (P<0.05 and P<0.01). In the WB analysis, the protein levels of CYP7A1 and CYP8B1 in the A-SP-i.g. group were decreased compared with those in the control group, similar to those in the ANIT group. In the A-SP-i.p. group, these levels were almost identical to those in the control group (Fig. 3C).
Organic anion-transporting polypeptide 1 (OATP1), heteromeric organic solute transporter β subunit (OSTB), multidrug resistance 2 (MDR2) and multidrug resistance 1A (MDR1A) are involved in bile acid efflux (25). OATP1 was decreased, and OSTB, MDR2, MDR1A were all increased by ANIT treatment. However, no difference of these transporters was observed among the A-SP-i.p., A-SP-i.g. and ANIT groups. The changes in bile acid transporters were similar in the three groups challenged by ANIT, which was mainly considered to be adaptive responses (Fig. 4A-D). Other genes involved in bile acid metabolism were not obviously affected (data not shown).
Differential inflammation responses between the two administration routes
The mRNA expression levels of IL-6, IL-1β and ICAM-1 was revealed to be significantly increased following ANIT treatment (Fig. 5A-C, P<0.05, P<0.001 and P<0.01). IL-6 and IL-1β mRNA levels were decreased in the A-SP-i.p. and A-SP-i.g. groups, but the decrease was greater in the A-SP-i.p. group compared with the ANIT group. The protective inflammation factor IL-10 was upregulated in the ANIT and A-SP-i.g. groups compared with the control group, which was not observed in the A-SP-i.p. group (Fig. 5D). In terms of apoptosis, the BCL2 and P53 mRNA levels were increased following administration of ANIT at 75 mg/kg, but both were suppressed by pretreatment with SP600125, without a significant difference between the two administration routes (Fig. 5E and F). These data indicated that inflammation developed in the mice challenged with ANIT, but it was differentially blocked by i.p. and i.g. administration of SP600126.
SP600125 i.p. inhibits JNK signaling
The c-JUN and c-FOS mRNA levels were increased by ANIT. Compared with the ANIT group, the c-JUN mRNA was decreased in the A-SP-i.p. group (P<0.05), but not in the A-SP-i.g. group (Fig. 6A). The c-FOS mRNA was decreased in both the A-SP-i.p. and A-SP-i.g. groups, and this decrease was greater in the A-SP-i.p. group (Fig. 6B, P<0.01 and P<0.05). The WB analysis revealed that the p-MKK4 was activated in the ANIT, A-SP-i.p. and A-SP-i.g. groups and p-JNK was activated in the ANIT group compared with the control group. This pathway was strongly inhibited in the A-SP-i.p. group, but only partly inhibited in the A-SP-i.g. group. Activation of p-c-Jun was observed in the ANIT group, but it was markedly inhibited by SP600125 in the A-SP-i.p. group, in which liver injury was not observed (Fig. 6C). Thus, SP600125 acted against ANIT-induced cholestatic liver injury following i.p. administration. The aforementioned protective effect and differential inflammation regulation were attributed to the inhibition of JNK signalling following i.p. administration.
SP600125 exposure assessment
The multiple reaction monitoring mode was used to detect the negative ion transition m/z 191/219 for SP600125 (Fig. 7A and B). The calibration curve demonstrated a good linear association (R2>0.99) with satisfac-tory chromatographic performance (Fig. 7C). The mean plasma concentration-time profiles after a single administration of SP600125 (15 mg/kg i.p. and i.g.) are presented in Fig. 7D. The AUC0-24 of SP600125 was 31.05±2.53 and 19.82±4.57 µg h/ml, and the Cmax was 29.01±6.64 and 5.75±1.06 µg/ml by i.p. and i.g. administration, respectively. Thus, the exposure level of SP600125 in the ANIT-SP-i.p. group was significantly higher compared with that in the ANIT-SP-i.g. group treated with SP600125.
Discussion
Cholic acid, deoxycholic acid and typical pro-inflammatory cytokines can activate JNK signalling (21,26). The JNK pathway has been reported to regulate the bile acid metabolism (21,23,27). This pathway was activated in cholestatic mice challenged by ANIT and its activation profile was revealed to be correlated with cholestasis and liver injury (26). In the present study, a cholestatic liver injury model was induced by ANIT in mice, and the successful construction of the model was confirmed by serum biochemistry. Obvious loss of cellular boundaries, degenerative changes and marked necrosis were observed in the ANIT group. As anticipated, JNK signalling was activated when cholestasis was induced by ANIT.
The balance among synthesis, uptake and export of bile acids contributes to bile acid homeostasis (25). Bile acids are endogenous ligands for the farnesoid X receptor (FXR), which decreases their synthesis by the SHP-mediated suppression of the genes encoding CYP7A1 and CYP8B1 (27). The activated JNK downregulated the expression of CYP7A1 and CYP8B1 in primary rat hepatocytes (23). In human hepatocytes, FXR induced the expression of fibroblast growth factor 19, a secreted protein that suppresses CYP7A1 through a JNK-dependent pathway (28). In the present study, CYP7A1 and CYP8B1 were downregulated in the cholestatic groups induced by ANIT, while they were not altered in the A-SP-i.p. group, in which JNK signalling was inhibited. Therefore, the downregulation of CYP7A1 and CYP8B1 in the ANIT and A-SP-i.g. groups was the result of both adaptation and JNK-dependent inhibition. CYP7A1 and CYP8B1 levels were not affected in the A-SP-i.p. group, in which cholestasis was also induced and the JNK pathway was inhibited. This indicated the dependence of FXR-mediated adaptation on JNK activation, which was in agreement with previously reported findings (29). These data suggested that i.p. administration strongly inhibited JNK signalling and blocked adaptation of synthesis (Fig. 8).
The basolateral uptake transporters, OATP1 transports bile acids from the portal blood into hepatocytes; The basolateral efflux transporter MDR is involved in export of bile acids into the blood and OSTB exports bile acids into canaliculi (25). Bile acids activate FXR, which in turn accelerates bile acid export by inducing BSEP and OSTβ expression, and decreases bile acid uptake by suppressing sodium taurocholate co-transporting polypeptide and OATP expression (30). In the present study, the changes in the bile acid transporters OATP1, OSTB, MDR1A and MDR2 were similar among the three groups challenged by ANIT, which were considered as adaptive responses. This indicated that the FXR-mediated transport adaptation was independent of JNK activation, which was different from the synthesis adaptation indicated above.
In the present study, JNK signalling was activated in the ANIT group, but only partially inhibited in the SP-A-i.g. group, as indicated by the increase in p-MKK4, p-JNK and c-Jun in the WB analysis. This serial activation triggered liver injury, which was substantially attenuated when JNK signalling was more markedly inhibited in the SP-A-i.p. group compared with the SP-A-i.g. group. In the present study, SP600125 protected against cholestatic liver injury, as indicated by the regulation of bile acid metabolism, normalization of serum ALT, AST, and ALP levels and histomorphology in the A-SP-i.p. group. Thus, the administration route was found to be crucial for the inhibitory effect of SP600125 on the JNK pathway, which contributed to inhibition of the cholestatic liver injury.
As a JNK inhibitor, SP600125 has been widely used to investigate pathophysiological and pharmacological mechanisms (31). Its concentration used in cellular experiments was usually between 25 and 50 µM (5.5-11 µg/ml). In in vivo models of i.g. and i.p. administration, the dose range was 5-30 mg/kg (32,33). Unfortunately, no studies to date have explored the plasma exposure profile of SP600125. In the present study, the exposure of SP600125 by i.p. injection was significantly higher compared with that by i.g. injection and produced very different exposure profiles. The AUC0–24 (31.05 vs. 19.82 µg h/ml) and Cmax (29.01 vs. 5.75 µg/ml) were statistically significantly different between the two administration routes. The small Tmax (0.5-1 h) indicated the high potential of SP600125 to be absorbed and distributed. Thus, the in vivo exposure level of SP600125 was close to the concentration of SP600125 used in in vitro models. In the ANIT-SP-i.p. group, the duration of an SP600125 concentration >5.5 µg/ml was markedly longer compared with that in the ANIT-SP-i.g. group. In cellular models, SP600125 as a competitive inhibitor inhibited the phosphorylation of c-Jun in a dose-dependent manner (33). It may be reasonably inferred that SP600125 at a high concentration binds more JNK and inhibits its signalling. Therefore, the administration route of SP600125 determined its exposure level, and thereby the inhibition of JNK signalling (Fig. 8).
Collectively, the findings of the present study indicated that an effective dose-exposure level was crucial for the inhibitory effect of SP600125 on the JNK pathway, and i.p. administration was more effective compared with i.g. administration. This optimized regimen of SP600125 may lead to an improved design for future in vivo investigations. However, the dose-effect relationship in i.p. administration remains to be investigated for strongest inhibition of JNK signalling without toxic action.
Supplementary Data
Acknowledgments
Not applicable.
Funding
The present study was supported by the Ningbo Natural Science Foundation (grant nos. 2018A610253 and 2018A610384), the Ningbo Public Welfare Project (grant no. 202002N3160), the Zhejiang Public Welfare Technology Research Program (grant no. LGD19H070001), the Zhejiang Provincial Natural Science Foundation of China (grant no. LY20H030001) and the K.C. Wong Magna Fund of Ningbo University.
Availability of data and materials
The datasets used during the current study are available from the corresponding author on reasonable request.
Authors' contributions
XZ, MD, JY and AL participated in the research design, conducted experiments, performed data analysis and wrote the manuscript. GX conducted experiments and performed data analysis. LC performed data analysis and contributed new reagents or analytic tools. All authors read and approved the final version of the manuscript to be published.
Ethics approval and consent to participate
All experiments were approved by the Animal Care and Use Committee of Ningbo University.
Patient consent for publication
Not applicable.
Competing interests
Not applicable.
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