Abstract
MOLECULAR CELLULAR BIOLOGY ANIMAL CELLS AND SYSTEMS 2020, VOL. 24, NO. 2, 69–78 https://doi.org/10.1080/19768354.2020.1735518 JAK2-STAT5 signaling is insensitive to porcine growth hormone (pGH) in hepatocytes of neonatal pig Yang Yu-Jiang, Zheng Xin and Lan Hai-Nan College of Animal Science and Technology, Jilin Agricultural University, Changchun, People’s Republic of China ABSTRACT ARTICLE HISTORY Received 29 August 2019 Porcine growth hormone (pGH) is most important hormone which is involved in the growth and Revised 17 December 2019 development of pig. However, a series of studies have indicated that neonatal pig is insensitive Accepted 10 February 2020 to pGH; the reason for this phenomenon is still not fully understood. In this work, we try to investigate this issue from the angle of intracellular signaling induced by pGH. In the present KEYWORDS study, porcine hepatocytes from neonatal pig were used as a model, and confocal laser scanning Porcine growth hormone; microscopy (CLSM), Western blot, co-immunoprecipitation and colocalization assay were used to growth hormone receptor; study pGH’s signaling properties in hepatocytes of neonatal pig and explore the possible JAK2-STAT5/3/1; neonatal mechanism(s) for why intracellular signaling is insensitive to pGH. The results indicated that pig; porcine hepatocytes Janus kinase 2 and signal transducers and activators of transcription 5/3/1 (JAK2-STATs) signaling are not activated. We further investigated the possible mechanism(s) by which JAK2-STATs’ signaling is not activated by pGH and growth hormone receptor (GHR) and found that the negative regulatory molecules of JAK2-STATs signaling may be associated with this phenomenon in the hepatocytes of neonatal pig. In addition, we also explored pGH’s biology in hepatocytes from neonatal pig, it can be found that pGH/GHR could translocate into the cell nucleus, which implies that pGH/GHR may exhibit physiological roles based on their nuclear localization. We found that pGH could not trigger intracellular signaling in the hepatocytes of neonatal pigs, but not young pigs, which provides an important explanation for why the growth of neonatal pig is GH independent. Introduction effects, the latter is mediated by pGH-induced insulin like growth factor I (IGF-I) (Daughaday and Rotwein Growth hormone (GH) plays important roles in the regu- 1989). The liver is a major target organ of GH and it is lation of growth and development in mammals (Lan generally believed that the liver is the main source of et al. 2017). GH exerts its physiological functions by IGF-I in the circulation under pGH stimulation (Butler binding to growth hormone receptor (GHR) (Brooks and Roith 2001). pGH is the most important hormone and Waters 2010). It is generally believed that GH that regulates postnatal somatic growth of pig (Wester binding to GHR may induce GHR to produce special con- et al. 1998). However, it is interesting that pGH displaying formation change(s). Subsequently, Janus Kinase 2 (JAK2) its bioactivities is closely related to the physiological is activated by tyrosine phosphorylation, which sub- phases of pig. It has been reported that the growth of sequently phosphrylated signal transducer and activator neonatal pig is GH independent (Mbler et al. 1992; of transcription (STAT) and extracellular regulated Harrell et al. 1994). However, some studies have also indi- protein kinases (ERK1/2) ERK1/2 (Brooks et al. 2014; cated that neonatal pig is responsive to pGH, but the Waters 2016). These active signaling proteins transport response level is weaker than that of adult pigs. In into the cell nuclei, where they regulate gene expression. addition, although pGH could stimulate the liver of neo- It has been demonstrated that porcine growth natal pig to express IGF-1 mRNA and improve the level of hormone (pGH) increases growth rate, improves feed circulating IGF-1, the ability of the production of IGF-1 is efficiency, protein synthesis and increases muscle weaker than that of young pig (Rehfeldt et al. 2004). Fur- growth markedly (Chung et al. 1985; Evock et al. 1988). thermore, the concentration of pGH in the circulation of pGH is considered to display its physiological effects neonatal pig is very low (Lan et al. 2015), and pGHR through two ways, namely direct effects and indirect CONTACT Lan Hai-Nan zhengtougao@163.com College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, People’s Republic of China © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 70 Y.-J. YANG ET AL. expression also can be detectable in many tissues of neo- 5 min. The resulting hepatocytes were then adjusted to natal pig, such as the liver, muscle and bone (Wester et al. proper concentration and seed into cell culture plates. 1998). To date, the reason why pGH is insensitive in neo- The study was approved by the Animal Ethical Commit- natal pig remains to be fully understood. tee of Jilin Agricultural University. pGH was conjugated The aim of the present study is (1) to explore intra- to FITC, according to previous protocols (Lan et al. 2015). cellular signaling induced by pGH in the hepatocytes of neonatal pig; (2) to find a possible answer for why pGH is not sensitive in neonatal pig from the angle of pGH- Analysis of pGHR expression on porcine induced intracellular signaling. Porcine hepatocyte is an hepatocyte important target cell of pGH and also is an ideal To evaluate pGHR expression, Western-blot was per- somatic cell model to study pGH-induced intracellular formed. Freshly isolated hepatocytes were washed signaling (Lan et al. 2015). Therefore, in the current three times with ice-cold PBS. The cells were then trans- study, we isolated porcine hepatocytes of neonatal ferred on ice and lysed in RIPA lysis buffer containing pigs (1–7 days old). We found that pGH could not protease inhibitor cocktail. The samples were then col- trigger intracellular signaling in the hepatocytes of neo- lected by centrifugation. The cell lysates were resolved natal pig, but not young pigs. by SDS-PAGE and transferred to PVDF membranes. After blocking with 3% BSA for 60 min, the membranes were incubated with anti-pGHR antibody, control anti- Materials and methods body or anti-β-actin antibody for 60 min. After three Antibody and reagent washes, the membranes were incubated with horse- radish peroxidase conjugated secondary antibody. Porcine growth hormone and fluorescein isothiocyanate After washing with PBST for three times, the immuno- (FITC) were purchased from Sigma (St. Louis, MO, USA). reactive protein bands were detected by using an ECL Phospho-JAK2 and JAK2 were from Cell Signaling Tech- plus kit. nology (Danvers, MA, USA). Phospho-STAT5/3/1 and total STAT5/3/1 antibodies were obtained from Santa Cruz (Santa Fe County, New Mexico, USA). PVDF mem- Analysis of intracellular signaling in the branes, ECL and BSA were from Millipore. Porcine GHR, hepatocytes of neonatal pig β-actin and normal mouse/rabbit lgG were obtained from Abcam (Cambridge, England). Cell culture plates Western-blotting was performed to check the expression (6, 12 and 24 well format) were purchased from level of intracellular signaling proteins, according to our Corning Costar (Cambridge, MA, USA). Fetal calf serum previous methods (Lan et al. 2017). The Western-blot (FCS) was obtained from Invitrogen (Carlsbad, CA, USA). experiments were divided into two parts. First, the Lysis buffer was purchased from Beyotime Biotechnol- expression levels of signaling proteins (namely total pro- ogy (Shanghai, China). Collagenase was obtained from teins) were analyzed. Secondly, the phosphorylation Hua Cheng Biological Inc (Changchun, China). All other levels of intracellular signaling proteins were evaluated. reagents were purchased from Sigma (St. Louis, MO, In brief, the culture media of porcine hepatocytes were USA). replaced with serum-free media for 4 h before the exper- imental treatments. The porcine hepatocytes were stimulated with pGH for 30 min at 37°C, after which, Isolation and culture of porcine hepatocytes the porcine hepatocytes were solubilized. The protein Porcine hepatocytes were isolated according to our pre- samples were then collected, and the protein concen- vious methods (Lan et al. 2017). In brief, the pigs (Land- trations were determined using a BCA protein assay kit. race, 1–7 days old and 100 days old) were stunned and The samples were resolved by SDS-PAGE and transferred exsanguinated. The left liver lobes were cut. A cannula to PVDF membranes. After blocking with 3% BSA for was inserted into the portal vein of the porcine liver. 60 min, the membranes were incubated with indicated The porcine livers were first perfused with physiological antibodies for 60 min. After washing three times with saline buffer to remove out blood cells. The livers were PBST, the membranes were incubated with horseradish then perfused with the collagenase. Following perfusion, peroxidase (HRP)-conjugated secondary antibody for the left lateral lobes of porcine livers were excised and 60 min. After washing with PBST for three times, the minced. The resulting hepatocyte suspension was immunoreactive protein bands were detected by using filtered through a 100 µm nylon mesh. The porcine hep- an ECL plus kit. The membranes were incubated with atocytes were collected by centrifugations at 50 g for stripping buffer solution for 30 min at 55°C. The ANIMAL CELLS AND SYSTEMS 71 membranes were then blocked and re-probed for signal- durations. The porcine hepatocytes were then washed ing proteins. for three times with PBS and fixed with 4% paraformalde- hyde at 37°C for 20 min. After washing, the cell nuclei were stained with DAPI. After washing for three times Laser scanning confocal microscope (CLSM) with PBS, the cells were observed using confocal laser analysis scanning microscopy (Olympus FV3000); (2) for colocali- zation analysis, the cells were fixed and blocked, the cells Freshly isolated porcine hepatocytes were placed on were then treated with the indicated antibodies. After glass cover slips in 6-well cell culture plates and main- washing, the cells were incubated with second anti- tained in serum-free culture media for 2 h. The cells bodies labeled with Alexa Fluor 488 (green) and Alexa were treated as follows: (1) for pGH internalization analy- Fluor 555 (red). After washing for three times, the cells sis, the cells were washed with PBS, the FITC-pGH were were observed using CLSM. then added into the plates and incubated for different Figure 1. (A) pGHR expression on the hepatocytes from 1 to 7 days old and 100 days old pig. The freshly isolated hepatocytes were pre- treated, as described as in materials and methods. The cells were then incubated with anti-pGHR antibody. After washing three times, the cells were treated with FITC-labeled secondary antibody. Bar: 10 μm. (B) Characterization of pGHR expression by Western blot. The cell extracts from porcine hepatocytes were subjected to immunoblotting with anti-pGHR antibody. After incubation with secondary antibody at room temperature, the immunoreactive bands were detected using an ECL-plus kit. (C) Comparison of pGHR expression between 100 days old pig and 7 days old pig. Data are shown as the mean ± SE. Significant differences are marked with an asterisk. The figure is representative of three independent experiments. 72 Y.-J. YANG ET AL. Statistics expression has no change in the hepatocytes of 1–7 days old pig (Figure 1(B)). In addition, pGHR expression The data are presented as the mean ± standard error from hepatocytes of 100 days old pig is higher than (S.E.). The results were analyzed by one-way analysis of that of 7 days old pig (Figure 1(C)). variance using Statistical Analysis System (SAS) software (SAS version 9.0; Institute Inc., Cary, NC, USA). A p-value <0.05 was considered statistically significant. Intracellular signaling proteins expression We first check the expression level of signaling molecules (JAK2, STAT5) in the hepatocytes of neonatal pigs. As Results shown in Figure 2, the hepatocytes from 1 to 7 days pGHR expression on the hepatocytes of neonatal old pigs expressed a similar level of JAK2 and STAT5 pigs with that of 100 days (∼60 kg). Therefore, porcine hep- atocytes from 1, 3, 7 and 100 days pigs were used at We first preliminarily evaluate hepatic cell surface GHR the following experiments. expression in the hepatocytes of 1–7 days old and 100 days old pig by CLSM, as indicated in Figure 1(A). The results indicated that GHRs were expressed on the cell JAK2 activation induced by pGH in the cytoplasm and membrane, and there were no difference hepatocytes of neonatal pig in the pGHR expression levels in 1–7 days old pig. In addition, pGHR expression was also evaluated by Previous studies have reported that the hepatocyte of Western blotting; the results indicated that the pGHR growing young pig (∼60 kg) is very sensitive to pGH Figure 2. Analysis of signaling protein expression in the hepatocytes obtained from 1 to 7 days old and 100 days old pig. The cell extracts from porcine hepatocytes were subjected to immunoblotting with the indicated antibodies. After incubation with secondary antibody at room temperature, the immunoreactive bands were detected using an ECL-plus kit. The figure is representative of three independent experiments. ANIMAL CELLS AND SYSTEMS 73 (Lan et al. 2015). Therefore, in the current study, the hep- data, we study JAK2 activation under pGH stimulation atocytes of 100 days old (∼60 kg) were used as a positive in neonatal hepatocytes under the same culture con- control. In our previous study, JAK2 activation displayed ditions. We can see from Figure 3 that pGH cannot acti- a time-dependent manner (0–60 min). Based on these vate JAK2 in time-course experiments in neonatal Figure 3. Dose-response and time-course of STAT5 phosphorylation activated by pGH. For dose-response experiments, the cell extracts from porcine hepatocytes obtained from 1 to 7 days old and 100 days old pig were stimulated with increasing concentrations of pGH (0–45 nM) for 30 min, after which, the cell extracts were subjected to immunoblotting with the anti-pJAK2 or anti-total JAK2. After incubation with secondary antibody, the immunoreactive bands were detected using an ECL-plus kit; for time-course experiments, the cell extracts from porcine hepatocytes obtained from 1 to 7 days old and 100 days old pig were treated with constant pGH for different durations at 37°C (0–60 min). After washing for three times, the cellular proteins were solubilized and subjected to immuno- blotting with the anti-pJAK2 or anti-total JAK2. The figure is representative of three independent experiments. 74 Y.-J. YANG ET AL. hepatocytes. In contrast, JAK2 phosphorylation level hepatocytes under the same culture conditions. As obviously elevated after pGH stimulation for 15 and shown in Figure 4, pGH cannot induce STAT5/3/1 phos- 30 min. phorylation in dose- and time-dependent experiments in neonatal hepatocytes. In contrast to neonatal hepato- cytes, STAT5/3/1 was strongly activated under pGH STATs phosphorylation induced by pGH in the stimulation in a dose- and time-dependent manner. hepatocytes of neonatal pig Subsequently, STAT5/3/1 activation was accessed. Exploration of possible mechanisms for JAK2- Similar to JAK2, our previous experimental and others STATs’ signaling insensitivity have reported that the hepatocytes of growing young pig (60 kg) are very sensitive to pGH, which exhibits sen- We first checked the interactions between pGH and GHR sitive STATs’ signaling response in time-course exper- by CLSM; we can see that pGH and GHR could interact iments. Based on this, we investigated STAT5/3/1 with each other on the cells, which indicated that pGH activation under pGH stimulation in neonatal could interact normally with GHR (Figure 5(A)). Figure 4. Dose-response and time-course of STAT5/3/1 activation induced by pGH in the hepatocytes obtained from 1 to 7 days old and 100 days old pig. For dose-response experiments, the cell extracts from porcine hepatocytes obtained from 1 to 7 days old and 100 days old pig were stimulated with increasing concentrations of pGH (0–45 nM) for 30 min, after which the cell extracts were subjected to immunoblotting with the anti-pSTAT5/3/1 or anti-total STAT5/3/1. After incubation with secondary antibody for 1 h, the immuno- reactive bands were detected using an ECL-plus kit; for time-course experiments, the cell extracts from porcine hepatocytes obtained from 1 to 7 days old and 100 days old pig were treated with constant pGH for different durations at 37°C (0–60 min). After washing for three times, the cellular proteins were solubilized and subjected to immunoblotting with the anti-pSTAT5/3/1 or anti-total STAT5/3/1. The figure is representative of three independent experiments. ANIMAL CELLS AND SYSTEMS 75 Figure 5. Exploration of possible mechanisms for JAK2-STAT5 signaling insensitivity. A. pGH could interact normally with GHR in the hepatocytes of neonatal pig. The cells were then washed for three times with PBS and fixed with 4% paraformaldehyde at 37°C for 20 min. The cells were then treated with the indicated antibodies. After washing, the cells were incubated with second antibodies labeled with Alexa Fluor 488 (green) and Alexa Fluor 555 (red). The cells were observed using confocal laser scanning microscopy (CLSM). Bar: 10 μm. B. pGH/GHR lacks the ability to recruit and activate intracellular signaling molecule. C. The plasma membrane-loca- lized GHR was not activated by pGH in hepatocytes of neonatal pig. D. The expression of negative regulatory molecules for JAK2-STAT5 signaling. E. SOCS1 could interact with JAK2/GHR complex in the hepatocytes of neonatal pig. The above-mentioned study has shown that pGH phosphorylated in hepatocytes of neonatal pig in our could interact normally with GHR. We then analyzed if experimental conditions (Figure 5(C)). pGH/GHR could recruit intracellular signaling molecules Next, we further explore why GHR was not activated in hepatocytes of neonatal pig, the results showed that by pGH in the hepatocytes of neonatal pig. Previous pGH/GHR lacks the ability to recruit and activate intra- studies have demonstrated that JAK2-STAT5 signaling cellular signaling protein (STAT5) (Figure 5(B)). Next, we pathway is regulated by negative regulatory molecules ask why pGH/GHR cannot recruit and trigger the intra- (such as tyrosine-phosphatases SHP-1,-2 and suppres- cellular signaling protein. It is well known that GHR phos- sors of cytokine signaling (CIS/SOCS)). Therefore, we phorylation is necessary for STAT5 activation; we, checked the expression of these negative regulatory therefore, tested whether GHR was phosphorylated molecules, as shown in Figure 5(D), SOCS1 was after pGH treatment, the results indicated that the highly expressed. To further test whether this negative plasma membrane-localized GHR was not regulatory molecule is involved in pGH/GHR signaling 76 Y.-J. YANG ET AL. Figure 6. pGH’s nuclear localization in the hepatocytes of neonatal pig. Freshly isolated porcine hepatocytes were placed on glass cov- erslips. After incubation with serum-free culture media for 3 h, the FITC-pGH were added into the plates and incubated for different durations. The cells were observed using confocal laser scanning microscopy (CLSM). Bar: 10 μm. The fluorescence intensity at the cell nuclei was determined by selecting the appropriate region of interest (ROI) using image J software (developed by NIH). The numeric data are presented as mean ± SD from at least three independent experiments with 30 cells each. ANIMAL CELLS AND SYSTEMS 77 insensitivity in the hepatocytes of neonatal pig, we considerably lower than that of mature pigs (Lewis performed IP and WB experiments, and the results et al. 2000). In the current study, we try to find a indicated that SOCS1 could interact with JAK2/GHR new explanation from the angle of pGH-induced intra- complex in the hepatocytes of neonatal pig (Figure 5 cellular signaling. We found that pGH cannot activate (E)). These observations suggest that SOCS1 could JAK2-STATs’ signaling in the hepatocytes of newborn play a role in the pGH/GHR signaling insensitivity in pigs under our experimental conditions (Figures 3 the hepatocytes of neonatal pig. and 4). However, pGH could strongly activate JAK2- Since pGH/GHR fails to activate the intracellular sig- STATs in porcine hepatocytes from 60 kg pigs. This naling pathway in the hepatocytes of neonatal pig, work suggests that weak or no signaling responsive- does it mean that pGH/GHR has no effect in neonatal ness may result in that pGH is not sensitive in pig? Traditional view believes that pGH/GHR exhibits newborn pigs. Although Lewis’s research has shown its physiological functions in cell membrane; that, in newborn pigs, IGF-I mRNA expression is however, recent studies also show that GH/GHR can weakly elevated in the liver and muscle under exogen- transport into cell nuclei, where they also can exert ous GH treatment, muscle may be more responsive to important roles (such as proliferation) (Conway-Camp- GH than the liver in this physiological stage (namely bell et al. 2007). Therefore, GHR’s nuclear localization newborn pigs) (Lewis et al. 2000), which suggests induced by GH should be a potential parameter for that, in newborn pigs, IGF-1 in the circulation was evaluating pGH/GHR’s activity except for intracellular mainly derived from muscle or other organ, but not signaling. Here, we preliminarily investigated pGH’s liver. This suggests that the main source of IGF-1 is nuclear translocation in the hepatocytes of neonatal different in different physiological stages; this implies pig. As shown in Figure 6, pGH could translocate a complementary mechanism among different tissues into cell nuclei of hepatocytes of neonatal pig, may exist, by which the level of plasma IGF-1 maintains which suggests that, in this physiological stage a normal physiological status. (namely newborn pigs), pGH could exhibit its func- GH is considered to display its physiological effects tions based on its nuclear localization in hepatocytes through two ways, direct effects and indirect effects, of neonatal pig. the latter is mediated by the insulin like growth factor I (IGF-I) (Sjögren et al. 1999). The liver is believed to be the primary source of circulating IGF-I Discussion (Le et al. 2001). The IGF-I gene expression is regulated Although pGH is one of the most important hormones by JAK2-STAT5 signaling pathway. In this work, JAK2- that regulates porcine postnatal growth and develop- STAT5 signaling is undetectable in the hepatocytes ment, many studies indicated that neonatal pig is from newborn pigs, which provide a possible expla- irresponsive or insensitive to pGH in neonatal pig nation for low IGF-1 expression in newborn pigs. (Harrell et al. 1994; Rehfeldt et al. 2004). However, until Recently, a series of studies have shown that pGH now, the reason for this phenomenon remains to be not only exhibits its physiological roles in cell mem- fully understood. In this study, we try to investigate this brane but also exerts its biological activities by its problem from the angle of intracellular signaling nuclear translocation (Brooks et al. 2008). It has been induced by pGH. To our knowledge, this study shown that the nuclear-localized GHR exhibits a initially investigates pGH-induced intracellular signaling strong relation with cell’s high proliferation (Conway- pathway in the hepatocytes of neonatal pig. Campbell et al. 2007). In the current study, it can be In previous studies, the researchers have analyzed observed that pGH was rapidly translocated into the the reason for why GH is not sensitive in neonates; nucleus by CLSM, which suggests that pGH/GHR may they proposed that GHR’s expression is low in neonatal directly participate in cell proliferation. Based on animals, which leads to low GH binding, which, in turn, these, we propose a new paradigm for pGH/GHR’s results in low circulating IGF-1 (Martinez et al. 2013). roles, namely pGH may be mainly involved in liver However, Wester et al reported that they investigated cell proliferation but not in IGF-1 expression in neo- the effects of exogenous GH treatment on IGF-I level natal pig. in the circulation and found that IGF-I in the plasma In summary, in the current work, we found that is increased in vivo (Wester et al. 1998). In addition, JAK2-STATs signaling is not sensitive to pGH in Lewis et al indicated that exogenous GH administration newborn pigs, which provides a possible explanation results in increasing IGF-1 and GHR mRNA expression. for why pGH is unresponsive in newborn pigs. Based These results suggest that GH is responsive in neonatal on this, we propose a new paradigm for pGH’s func- pigs. However, the magnitude of the responses is tions in neonatal pig. 78 Y.-J. YANG ET AL. analog stimulate pig growth performance in a similar Disclosure statement manner. J Anim Sci. 66(8):1928–1941. No potential conflict of interest was reported by the author(s). Harrell RJ, Thomas MJ, Boyd RD. 1994. Ontogenic dependent response to exogenous porcine somatotropin in growing pigs (Abstract). J Anim Sci. 72:253. Funding Lan HN, Hong P, Li RN, Suo L, Shan AS, Zheng X. 2017. Growth hormone (gh)-specific induction of the nuclear localization This work was supported by the National Natural Science Foun- of porcine growth hormone receptor (pGHR) in the porcine dation of China-Young investigator grant program [grant hepatocytes. Domest Anim Endocrin. 61:61–67. number 31602022]. This project was partially supported by Lan HN, Jiang HL, Li W, Yang YH, Zheng X. 2015. Development Jilin Provincial Science & Technology Development Project and characterization of a novel anti-idiotypic monoclonal [grant number 20180520041JH]. This project was partially sup- antibody to growth hormone, which can mimic physiological ported by the Scientific Research projects of the Thirteenth functions of growth hormone in primary porcine hepato- Five-Year plan of Jilin Province Department of Education cytes. Asian Australas J Anim Sci. 28(4):573–583. [grant number JJKH20190905KJ]. Le RD, Scavo L, Butler A. 2001. What is the role of circulating IGF- I? 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Journal
Animal Cells and Systems
– Taylor & Francis
Published: Mar 3, 2020
Keywords: Porcine growth hormone; growth hormone receptor; JAK2-STAT5/3/1; neonatal pig; porcine hepatocytes
