Jia Sun
National University of Singapore
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Featured researches published by Jia Sun.
American Journal of Physiology-cell Physiology | 2008
Jia Sun; Raina Devi Ramnath; Liang Zhi; Ramasamy Tamizhselvi; Madhav Bhatia
The neuropeptide substance P (SP), as a major mediator of neuroimmunomodulatory activity, modulates diverse functions of immune cells, including macrophages. In the current study, we focused on the yet uncertain role of SP in enhancing the inducible/inflammatory chemokine response of macrophages and the signaling mechanism involved. We studied the effect on the murine monocyte/macrophage cell line RAW 264.7 as well as isolated primary macrophages. Our data show that SP, at nanomolar concentrations, elicited selective chemokine production from murine macrophages. Among the chemokines examined, macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 are two major chemokines that were synthesized by macrophages in response to SP. Furthermore, SP treatment strongly induced the classic pathway of IkappaB-dependent NF-kappaB activation and enhanced DNA binding as well as transactivation activity of the transcription factor. SP-evoked transcriptional induction of chemokines was specific, since it was blocked by treatment with selective neurokinin-1 receptor antagonists. Moreover, SP stimulation of macrophages activated the ERK1/2 and p38 MAPK but not JNKs. Blockade of these two MAPK pathways with specific inhibitors abolished SP-elicited nuclear translocation of phosphorylated NF-kappaB p65 and NF-kappaB-driven chemokine production, suggesting that the two MAPKs lie in the signaling pathways leading to the chemokine response. Collectively, our data demonstrate that SP enhances selective inflammatory chemokine production by murine macrophages via ERK/p38 MAPK-mediated NF-kappaB activation.
Journal of Cellular and Molecular Medicine | 2007
Raina Devi Ramnath; Jia Sun; Sharmila Adhikari; Madhav Bhatia
Substance P, acting via its neurokinin 1 receptor (NK1 R), plays an important role in mediating a variety of inflammatory processes. Its interaction with chemokines is known to play a crucial role in the pathogenesis of acute pancreatitis. In pancreatic acinar cells, substance P stimulates the release of NFκB‐driven chemokines. However, the signal transduction pathways by which substance P‐NK1 R interaction induces chemokine production are still unclear. To that end, we went on to examine the participation of mitogen‐activated protein kinases (MAPKs) in substance P‐induced synthesis of pro‐inflammatory chemokines, monocyte chemoanractant protein‐1 (MCP‐I), macrophage inflammatory protein‐lα (MIP‐lα) and macrophage inflammatory protein‐2 (MIP‐2), in pancreatic acini. In this study, we observed a time‐dependent activation of ERK1/2, c‐Jun N‐terminal kinase (JNK), NFκB and activator protein‐1 (AP‐1) when pancreatic acini were stimulated with substance P. Moreover, substance P‐induced ERK 1/2, JNK, NFκB and AP‐1 activation as well as chemokine synthesis were blocked by pre‐treatment with either extracellular signal‐regulated protein kinase kinase 1 (MEK1) inhibitor or JNK inhibitor. In addition, substance P‐induced activation of ERK 112, JNK, NFκB and AP‐1‐driven chemokine production were attenuated by CP96345, a selective NK1 R antagonist, in pancreatic acinar cells. Taken together, these results suggest that substance P‐NK1 R induced chemokine production depends on the activation of MAPKs‐mediated NFκB and AP‐1 signalling pathways in mouse pancreatic acini.
Experimental Cell Research | 2010
Ramasamy Tamizhselvi; Yung-Hua Koh; Jia Sun; Huili Zhang; Madhav Bhatia
We have earlier shown that mouse pancreatic acinar cells produce hydrogen sulfide (H(2)S), which plays a key role in the pathogenesis of acute pancreatitis (AP). H(2)S-dependent induction of inflammation is mediated by the activation of transcription factor NF-kappaB. We now provide evidence that activation of Src family kinases (SFKs) is crucial in signaling H(2)S-induced intracellular adhesion molecule (ICAM)-1 expression via NF-kappaB. Stimulation of acini with H(2)S resulted in a time-dependent activation of SFKs. In order to better understand this effect of H(2)S, acinar cells were stimulated with caerulein after addition of H(2)S donor, NaHS. Inhibition of SFKs impaired H(2)S-induced NF-kappaB activity and ICAM-1 expression in caerulein treated acinar cells. We also observed that H(2)S-induced up-regulation of ICAM-1 enhanced the adhesion of neutrophils onto acinar cells. Analysis of NF-kappaB pathway revealed that the effect of SFKs inhibition correlated with IkappaBalpha degradation and NF-kappaB DNA binding function. Interestingly, H(2)S-induced association of SFKs with translocation of NF-kappaB, and inhibition of SFKs prevented this response, indicating that this interaction may depend on activation of SFKs. These data suggest that H(2)S, by activating the phosphorylation of SFKs, may promote the transcriptional activity of NF-kappaB and eventually lead to an upregulation of ICAM-1 expression.
The FASEB Journal | 2009
Jia Sun; Raina Devi Ramnath; Ramasamy Tamizhselvi; Madhav Bhatia
Neuropeptide modulation of immune cell function is an important mechanism of neuroimmune intersystem crosstalk. Substance P (SP) is one such key neuropeptide involved. In this study, we investigated the yet unexplored cellular mechanisms of SP‐mediated inflammatory responses in macrophages using a mouse macrophage‐like cell line RAW 264.7 and isolated peritoneal macrophages. We found that the conventional PKCα and novel PKCδ and ε were selectively activated by SP via its primary neurokinin‐1 receptor (NK‐1R) on the cells. Activation of these PKC isoforms mediated the activation of downstream extracellular signal‐regulated kinase‐1/2 (ERK1/2) and the transcription factor NF‐κB, which drove the transcription of inducible chemokines in macrophages. Additionally, phosphoinositide 3‐kinase (PI3K)‐Akt was also activated by SP/NK‐1R in macrophages. Inhibition of PI3K‐Akt pathway attenuated ERK1/2 and NF‐κB activation, suggesting it also played a part in SP‐induced cellular inflammatory response. Kinetic analysis indicated that PKC isoforms induced early ERK1/2 activation, while PI3K‐Akt contributed to the pathway at later time points. It was further demonstrated that PKC and PI3K‐Akt were activated independent of each other. Collectively, our results suggest that SP/NK‐1R activates two convergent proinflammatory signaling pathways, PKCs and PI3K‐Akt, resulting in ERK1/2 and NF‐κB activation and chemokine production in mouse macrophages.—Sun, J., Ramnath, R. D., Tamizhselvi, R., Bhatia, M. Role of protein kinase C and phosphoinositide 3‐kinase‐Akt in substance P‐induced proinflammatory pathways in mouse macrophages. FASEB J. 23, 997–1010 (2009)
Journal of Pharmacology and Experimental Therapeutics | 2009
Ramasamy Tamizhselvi; Jia Sun; Yung Hua Koh; Madhav Bhatia
We have shown earlier that mouse pancreatic acinar cells produce hydrogen sulfide (H2S) and play a role in the pathogenesis of acute pancreatitis. It is noteworthy that recent evidence indicates that H2S has anti-inflammatory effects. To date, the mechanism by which H2S directly reduces inflammation has not been elucidated. In the present study, we hypothesized that H2S inhibits the production of proinflammatory cytokines by activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. Pancreatic acinar cells were treated with the H2S donor, sodium hydrogen sulfide (NaHS) (5, 10, and 30 μM). To better understand the effect of H2S in inflammation, pancreatic acinar cells were stimulated with caerulein after the addition of NaHS (5, 10, and 30 μM). We observed that H2Sat the 5 μM concentration down-regulates the activation of NF-κB and degradation of IκBα. However, H2S(5 μM) activates PI3K as reflected by AKT phosphorylation. We found that H2S-mediated activation of PI3K in caerulein-treated acinar cells correlated with the down-regulation of extracellular signal-regulated kinase 1/2 phosphorylation, whereas phosphorylation of p38 and c-Jun NH2-terminal kinase and mitogen-activated protein kinases was unchanged. The PI3K inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride] abolished the H2S-mediated activation of AKT and increases tumor necrosis factor α and interleukin 1β levels in caerulein-treated acinar cells. These findings indicate that the phosphatidylinositol 3-kinase plays a negative role in NaHS-treated pancreatic acinar cells and suggest a role for H2S in the PI3K/AKT pathway in acute pancreatitis.
Journal of Pharmacology and Experimental Therapeutics | 2009
Raina Devi Ramnath; Jia Sun; Madhav Bhatia
Substance P is known to play a key role in the pathogenesis of acute pancreatitis. Src family kinases (SFKs) are known to be involved in cytokine signaling. However, the involvement of SFKs in substance P-induced chemokine production and its role in acute pancreatitis have not been investigated yet. To that end, we have used primary preparations of mouse pancreatic acinar cells as our model to show that substance P/neurokinin 1 receptor (NK1R) induced activation of SFKs. SFKs mediated the activation of mitogen-activated protein kinases [extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK)], transcription factors [signal transducer and activator of transcription (STAT) 3, nuclear factor (NF) κB, activator protein-1 (AP-1)], and production of chemokines in pancreatic acinar cells. We further tested the significance of the SFK signaling pathway in acute pancreatitis. Our results show, for the first time, that treatment of mice with the potent and selective SFK inhibitor PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d] pyrimidine], but not its negative inhibitor PP3 (4-amino-7-phenylpyrazol [3,4-d] pyrimidine), reduced the severity of pancreatitis. This was proven by significant attenuation of hyperamylasemia, pancreatic myeloperoxidase activity, chemokines, and water content. Histological evidence of diminished pancreatic injury also confirmed the protective effect of the inhibition of SFKs. Moreover, treatment with the substance P receptor antagonist CP96345 [(2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine] attenuated acute pancreatitis-induced activation of SFKs, ERK, JNK, STAT3, NFκB, and AP-1. The proposed signaling pathway through which substance P mediates acute pancreatitis is through substance P/NK1R-SFKs-(ERK, JNK)-(STAT3, NFκB, AP-1) chemokines. In light of our study, we propose that drugs targeting the substance P-mediated signaling pathways could prove beneficial in improving treatment efficacy in acute pancreatitis.
American Journal of Physiology-cell Physiology | 2008
Jia Sun; Raina Devi Ramnath; Ramasamy Tamizhselvi; Madhav Bhatia
Neurokinin A (NKA) belongs to the tachykinin neuropeptide family. Its biological functions are primarily mediated by the neurokinin (NK)-2 receptor. NKA has been implicated in several inflammatory conditions. However, there are limited data about the mechanism of its pathogenetic action. Here, we investigated proinflammatory effects of NKA on peripheral immune cells using the mouse macrophage/monocyte cell line RAW 264.7 and primary peritoneal macrophages. The signaling mechanistic pathways involved were also studied. In mouse macrophages with no detectable NK-2 receptors, NKA induces the upregulation of NK-1 but not NK-2 receptor expression. Furthermore, NKA engages this NK-1 receptor, resulting in inflammatory-like responses involving activation of the transcription factor nuclear factor (NF)-kappaB and induction of NF-kappaB-responsive proinflammatory chemokine expression. NKA activates NF-kappaB as evidenced by induced phosphorylation (leading to degradation) of its inhibitory protein IkappaBalpha, increased cellular levels of the transactivation-active phospho(Ser(276))-p65 and its nuclear translocation, as well as enhanced DNA-binding activity of NF-kappaB. These responses are specifically inhibited by selective NK-1 receptor antagonists but not NK-2 receptor antagonists, thereby excluding the role of NK-2 receptor. Further investigation on the upstream signaling mechanisms suggests that two NF-kappaB-activating pathways (extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3-kinase/protein kinase B) are activated by NKA. Specific inhibitors of the two pathways block NF-kappaB-dependent chemokine expression. The inhibitory effects are mediated through regulation of nuclear translocation, DNA-binding activity, and/or transactivation activity of NF-kappaB. Together, we provide novel evidence that NKA engages NK-1 receptors on mouse macrophages to elicit NF-kappaB-dependent cellular responses. The findings reveal cellular mechanisms that may underlie NKA-mediated inflammatory and immunological conditions.
Oxidative Medicine and Cellular Longevity | 2016
Zhaojun Dong; Haixiao Shang; Yong Q. Chen; Li-Long Pan; Madhav Bhatia; Jia Sun
Acute pancreatitis (AP) is characterized by early activation of intra-acinar proteases followed by acinar cell death and inflammation. Cellular oxidative stress is a key mechanism underlying these pathological events. Sulforaphane (SFN) is a natural organosulfur antioxidant with undescribed effects on AP. Here we investigated modulatory effects of SFN on cellular oxidation and inflammation in AP. AP was induced by cerulean hyperstimulation in BALB/c mice. Treatment group received a single dose of 5u2009mg/kg SFN for 3 consecutive days before AP. We found that SFN administration attenuated pancreatic injury as evidenced by serum amylase, pancreatic edema, and myeloperoxidase, as well as by histological examination. SFN administration reverted AP-associated dysregulation of oxidative stress markers including pancreatic malondialdehyde and redox enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx). In acinar cells, SFN treatment upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and Nrf2-regulated redox genes including quinoneoxidoreductase-1, heme oxidase-1, SOD1, and GPx1. In addition, SFN selectively suppressed cerulein-induced activation of the nucleotide-binding domain leucine-rich repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome, in parallel with reduced nuclear factor- (NF-) κB activation and modulated NF-κB-responsive cytokine expression. Together, our data suggested that SFN modulates Nrf2-mediated oxidative stress and NLRP3/NF-κB inflammatory pathways in acinar cells, thereby protecting against AP.
British Journal of Pharmacology | 2008
Raina Devi Ramnath; Jia Sun; Madhav Bhatia
Substance P (SP) and chemokines play critical roles in acute pancreatitis. SP elevates cytosolic calcium in pancreatic acinar cells and elevated cytosolic calcium is thought to be an early event in the pathogenesis of acute pancreatitis. SP induces production of chemokines MCP‐1, MIP‐1α and MIP‐2 in pancreatic acinar cells, however the exact mechanism by which SP stimulates the production of these pro‐inflammatory mediators remain undetermined. The aim of the present study is to investigate the role of calcium in SP‐induced chemokine production in pancreatic acinar cells and to establish the signal transduction mechanisms involved.
Expert Opinion on Therapeutic Targets | 2016
Muhammad Shamoon; Yuanyuan Deng; Yong Q. Chen; Madhav Bhatia; Jia Sun
Introduction: Acute pancreatitis (AP) is an inflammatory disorder of the pancreas encompassing a cascade of cellular and molecular events. It starts from premature activation of zymogens with the involvement of innate immune system to a potential systemic inflammatory response and multiple organ failure. Leukocytes are the major cell population that participate in the propagation of the disease. Current understanding of the course of AP is still far from complete, limiting treatment options mostly to conservative supportive care. Emerging evidence has pointed to modulation of the immune system for strategic therapeutic development, by mitigating the inflammatory response and severity of AP. In the current review, we have focused on the role of innate immunity in the condition and highlighted therapeutics targeting it for treatment of this challenging disease. Areas covered: The current review has aimed to elaborate in-depth understanding of specific roles of innate immune cells, derived mediators and inflammatory pathways that are involved in AP. Summarizing the recent therapeutics and approaches applied experimentally that target immune responses to attenuate AP. Expert opinion: The current state of knowledge on AP, limitations of presently available therapeutic approaches and the promise of therapeutic implications of innate immune system in AP are discussed.