Most of our understanding of this compound comes from the oncologic literature. As the pathways of oncology and inflammation converge, new lessons can be taken from the cross discipline. Many of the same cytokines, chemokines, and molecular signals influencing cancer cells to grow also stimulate immune cells.

Chapter 3 first explores the role of EGCG as both a preventative as well as a therapeutic agent and its effect on the dextran sulfate sodium DSS mouse model of colitis. The influence of EGCG on immune cell function is then explored in chapter 4.

One novel approach in chapter 4 has to do with a focus on intestinal epithelial cells as agents of an immune response, and how EGCG impacts their function in that role.

Chapter 5 explores the impact of EGCG on bolstering barrier function, as this is an important aspect of inflammatory bowel disease that is often neglected when considering new approaches to treating IBD. Dryden, Jr. Electronic Theses and Dissertations. Paper Medical Immunology Commons.

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Impact of epigallocatechingallate EGCG , a broad-spectrum anti-inflammatory, in controlling intestinal factors contributing to inflammatory bowel disease. Author Gerald Wayne Dryden, Jr. Document Type Doctoral Dissertation. Department Microbiology and Immunology.

Chondrocytes were pretreated with EGCG 10 to μM for 2 h and then stimulated with IL-1β for 8 h for mRNA expression except for TNF-α mRNA which was done at 24 h and 24 h for protein production.

To determine whether this inhibition of gene expression also influenced the production of IL-6 protein culture supernatants were assayed using ILspecific ELISA. Effect of EGCG IL-6, IL-8 and TNF-α gene expression and production in IL-1β-stimulated human OA chondrocytes.

Chondrocytes were pretreated with EGCG 10 to μM for 2 h and stimulated with IL-1β for a, b 8 h or c, d, e , and f 24 h. Gene expression for IL-6, IL-8 and TNF-α was determined by quantitative RT-PCR normalized to GAPDH and then compared with the levels present in un-stimulated chondrocytes. Levels of IL-6, IL-8 and TNF-α in the culture supernatants were quantified by sandwich ELISA.

Value represents Mean ± SE of three different patients. EGCG, epigallocatechingallate; IL-interleukin; TNF, tumor necrosis factor. When culture supernatants were analyzed for IL-8 protein levels results were similar to those obtained with IL-8 mRNA expression.

NF-κB is an important transcriptional regulator of inflammatory gene expression and plays a crucial role in immune and inflammatory response. However, activation of MAPKs is also intimately associated with the expression of pro-inflammatory genes. As IL-6, IL-8 and TNF-α genes are NF-κB dependent; its inhibition by EGCG provides an explanation for the inhibition of IL-6, IL-8 and TNF-α expression in OA chondrocytes.

EGCG also inhibited the activation of JNK in OA chondrocytes Figure 5b [ 13 ]; we also studied the role of MAPKs in IL-1β-induced expression of IL-6, IL-8 and TNF-α in OA chondrocytes. We used the pharmacological agents, MG NF-κB inhibitor , SB pMAPK inhibitor , SP JNK-MAPK inhibitor and PD ERK inhibitor to dissect the role of individual MAPKs in the expression of IL-6, IL-8 and TNF-α in OA chondrocytes.

When the role of individual MAPKs inhibition and expression of IL-6, IL-8 and TNF-α in OA chondrocytes was studied, we found that the activation of pMAPK was essential for the optimal expression of IL-6, IL-8 and TNF-α as inhibition of pMAPK nearly obliterated their expression in IL-1β-treated OA chondrocytes Figures 5 c, d and 5e.

Inhibition of ERK activation showed virtually no inhibition of IL-6, IL-8 and TNF-α gene expression in IL-1β-treated OA chondrocytes indicating that ERK activation is not essential for their expression. Thus, inhibitory effects of EGCG on IL-6, IL-8 and TNF-α expression may be related to the inhibition of NF-κB and JNK activation in IL-1β-stimulated OA chondrocytes.

These results also demonstrate that inhibition of IL-6, IL-8 and TNF-α can also be targeted via inhibition of pMAPK without inhibiting NF-κB. EGCG mediated inhibition of NF-κB and MAPKs in IL-1β stimulated human OA chondrocytes and regulation of IL-6, IL-8 and TNF-α. a Human OA chondrocytes were pretreated with EGCG 10 to μM for 2 h and stimulated with IL-1β for 24 h.

NF-κBp65 was determined in cell lysate by highly sensitive and specific ELISA Assay design. TNF-α-treated extract of HeLa cells supplied with the kit was used as a positive control.

The assay is developed with a chemiluminescent substrate and the signal is detected using luminometer Lumat LB ; Berthold Technologies. NF-κB p65 activity was expressed as relative light unit RLU. b After pretreatment with EGCG 10 to μM for one hour, chondrocytes were stimulated with IL-1β for one half-hour, and then phosphorylation of JNK, ERK and pMAPK was determined by Western immunobloting.

c, d , and e Effect of specific inhibitors for mitogen activated protein kinases and NF-κB on the gene expression of IL-6, IL-8 and TNF-α in IL-1β stimulated human OA chondrocytes. Primary chondrocytes were pretreated with specific inhibitors for 2 h and were stimulated with IL-1β for 6 h.

Relative gene expression of IL-6, IL-8 and TNF-α normalized to GAPDH and compared with un-stimulated control, were determined by quantitative RT-PCR.

Concentrations of specific inhibitors of p38 SB , JNK SP , ERK PD and NF-κB MG used in these studies were μM, 10 μM, 50 μM and μM, respectively. EGCG, epigallocatechingallate;IL-interleukin; ERK, extracellular signal-regulated kinases; JNK, cJun-N-termial Kinases; MAPKs, mitogen activated protein kinases; NF-κB, nuclear factor kappa-B; TNF, tumor necrosis factor.

TRAF-6 and IRAK-1 are important signaling intermediates in transducing signals to the cell after the binding IL-1 to IL-1R on the cell surface. OA chondrocytes were pretreated with EGCG 10 to μM for one hour and then stimulated with IL-1β for one half-hour for both mRNA expression and protein production.

EGCG pretreatment did not show any significant change on IRAK-1 mRNA expression in OA chondrocytes stimulated with IL-1β Figure 6c. Gene expression and production of TRAF-6 and IRAK-1 in IL-1β-stimulated human OA chondrocytes.

a and c Effect of EGCG pretreatment on the gene expression of TRAF-6 and IRAK-1 in IL-1β-stimulated OA chondrocytes, respectively.

b and d Effect of EGCG on the production of TRAF-6 and IRAK-1 in IL-1β-stimulated OA chondrocytes, respectively. Value represents Mean ± SD of three different patients. EGCG, epigallocatechingallate; IL, interleukin; IRAK-1, interleukin-1 receptor-associated kinase 1; TRAF-6, TNF receptor-associated factor 6.

In order to confirm the effects of EGCG obtained by protein array analysis, the expression of 15 additional genes was also analyzed by real-time PCR Figure 7a-o. The primer sequences for the genes verified by RT-PCR are given in Additional file 3. Among the genes whose expression was verified by real-time PCR analysis, EGCG appeared to inhibit the expression of GM-CSF, GRO, GRO-α and IP maximally in IL-1β-stimulated OA chondrocytes in agreement with the results shown above.

Real-time PCR verification of the expression of IL-1β. a , LIF b , IL-7 c , GM-CSF d , RANTES e , ENA f , GRO g , GRO-α h , MCP-1 i , MCP-2 j , MCP-3 k , MIP-1β l , IP m , GCP-2 n , NAP-2 o. ENA, epithelial neutrophil activating peptide; GCP-2, granulocyte chemotactic protein-2; GM-CSF, granulocyte-macrophages colony stimulating factor; GRO, growth-related oncogene; IL-interleukin; IP,10 kDa interferon gamma-induced protein; LIF, leukemia inhibitory factor; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; NAP-2, nucleosome assembly protein-2; RANTES, regulated upon activation normal T-cell expressed and secreted.

A large body of direct and indirect evidence links the NF-κB pathway to the inflammation and cartilage degeneration in OA. Thus, inhibition of NF-κB holds promise in regulating IL-1β-induced inflammatory response in human OA chondrocytes [ 3 , 26 ].

We also studied the effect of NF-κB inhibitor MG on the expression of LIF, IL-7, GM-CSF, ENA, GRO, GRO-α, MCP-1, MCP-2, MCP-3, MIP-1β, IP, GCP-2, and NAP Effect of specific inhibitors of MAPKs and NF-κB pathways on the gene expression of pro-inflammatory cytokines and chemokines in IL-1β-stimulated human OA chondrocytes.

Relative gene expression of LIF a , IL-7 b , GM-CSF c , ENA d and GRO e was normalized to GAPDH and compared with un-stimulated control, were determined by quantitative RT-PCR. ENA, epithelial neutrophil activating peptide; GM-CSF, granulocyte-macrophages colony stimulating factor; GRO, growth-related oncogene; IL-interleukin; LIF, leukemia inhibitory factor; MAPKs, mitogen activated protein kinases; NF-κB, nuclear factor kappa-B.

Effect of specific inhibitors of MAPKs and NF-κB pathways on the gene expression of pro-inflammatory chemokines in IL-1β-stimulated human OA chondrocytes. Relative gene expression of GRO-α a , MCP-1 b , MCP-2 c , MCP-3 d and MIP-1β e was normalized to GAPDH and compared with un-stimulated control, were determined by quantitative RT-PCR.

GRO, growth-related oncogene; MAPKs, mitogen activated protein kinases; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; NF-κB, nuclear factor kappa-B.

Relative gene expression of IP a , GCP-2 b and NAP-2 c was normalized to GAPDH and compared with un-stimulated control, were determined by quantitative RT-PCR. GCP-2, granulocyte chemotactic protein-2; IP, 10 kDa interferon gamma-induced protein; MAPKs, mitogen activated protein kinases; NAP-2, nucleosome assembly protein-2; NF-κB, nuclear factor kappa-B.

We have previously shown that EGCG inhibits JNK phosphorylation Figure 5b in IL-1β-stimulated OA chondrocytes but has no effect on p or ERK-MAPKs activation [ 13 ]. Here we examined the role of MAPKs in the regulation of the newly identified genes induced by IL-1β in OA chondrocytes and the possible role of EGCG in their modulation via MAPKs.

EGCG, a bioactive component of green tea has been shown to possess anti-cancer and anti-inflammatory activity with a potential for anti-arthritic effects and is of considerable interest in this regard [ 27 ].

Many cytokines have been implicated in causing synovial tissue activation and damage to cartilage and subchondral bone in OA [ 28 ]. The most widely investigated cytokine in OA is IL-1β, because it strongly induces cartilage catabolic agents [ 3 , 6 ], and inhibits proteoglycan and collagen synthesis [ 29 ].

In this study, a spectrum of biological effects of EGCG are described for the first time that provide evidence of modulation of cartilage protective and inflammation suppressing events by EGCG in IL-1β-stimulated OA chondrocytes.

In addition, several new genes were found to be induced by IL-1β in OA chondrocytes and their modulation by EGCG was studied. We used the larger screening capacity of the array technology to analyze for changes in cytokines levels induced by IL-1β in OA chondrocytes, and to search for their possible modulation by EGCG.

Our test system had limitations in that the screening was only limited to 80 cytokines broadly defined and some mediators with pathophysiological relevance to OA may have been neglected. However, the protein array technology is easy to use and supported by the specificity of protein recognition by antibodies.

Moreover, we used nitrite production as an indicator of chondrocytes activation by IL-1β and its suppression by EGCG [ 12 ], to demonstrate that the concentrations of IL-1β and EGCG used were sufficient to induce and detect the change in cellular response. Unlike the dramatic response of IL-1β alone, pre-incubation of chondrocytes with EGCG rendered the chondrocytes essentially unresponsive to subsequent IL-1β stimulation, and thereby EGCG appeared to be highly chondroprotective.

Our results showed the increased IL-1β levels in IL-1β stimulated OA chondrocytes, but EGCG pretreatment inhibited the IL-1β mRNA and protein levels in OA chondrocytes.

These results suggest that there may be a direct inhibitory effect of EGCG on IL-1β expression. Adaptor proteins involved in IL-1 signaling such as IRAK and TRAF-6, may also constitute important therapeutic targets for OA.

Phophorylated IRAK becomes associated with TRAF6, which is a downstream transducer required for NF-κB activation [ 31 ]. Our results showed that treatment with IL-1β caused a significant increase in TRAF-6 protein, whereas pre-incubation with EGCG inhibited the mRNA and protein expression of TRAF Autophosphorylation of IRAK promotes its dissociation from this complex, which is followed by its polyubiquitination, and subsequent degradation by the 26S proteosome system [ 32 , 12 ].

Our results showed that IL-1β-stimulation caused complete degradation of IRAK compared to control, whereas pre-incubation with EGCG inhibited IRAK degradation in OA chondrocytes.

This is important because our study identifies the EGCG mediated inhibition of IRAK degradation, a crucial event in the IL-1β-activated signal transduction pathway, in OA chondrocytes may be related to its anti-inflammatory activity as this may inhibit the signal transduction. Studies have reported the presence of IL-1β in diseased areas along with staining of TNF, IL-6 and IL-8 [ 33 , 34 ].

Evidence to date indicates that in addition to IL-1, IL-6, TNF-α and IL-8 can also promote articular cartilage extracellular matrix degradation or synergize with other cytokines to amplify and accelerate cartilage destruction [ 3 — 6 ].

Our array data showed that IL-1β-stimulation of OA chondrocytes significantly induced the mRNA as well as protein expression of IL-6, IL-8 and TNF-α, which was significantly down-regulated by EGCG.

Using highly sensitive ELISAs, we confirmed the array data which showed the significant dose dependent inhibitory effect of EGCG on the IL-1β-induced production of IL-6, IL-8 and TNF-α in OA chondrocytes.

This is supported by the previous study where EGCG was shown to inhibit IL-6 production in RA-synovial fibroblasts [ 35 ]. The pro-inflammatory pathways play central roles in the degradation of OA cartilage. IL-1β activates multiple phosphorylation-dependent signaling pathways including NF-κB and MAPKs that is, extracellular signal regulated kinase ERK , c-Jun N-terminal kinase JNK and pMAPKs , which lead to the coordinated expression of many genes that encode cytokines, chemokines, and other mediators involved in synthesis and further amplification of the inflammatory reaction [ 36 , 37 ].

We studied the involvement of NF-κB and MAPKs in IL-1β mediated inflammatory response and their regulation by EGCG.

Our data showed that EGCG inhibited the NF-κB activation and JNK-activation in IL-1β-stimulated OA chondrocytes as reported previously [ 12 , 13 ]. Data obtained from NF-κB inhibitor MG in the presence and absence of IL-1β revealed the role of NF-κB in the regulation of IL-6, IL-8 and TNF-α in OA chondrocytes.

Recent studies have suggested that the inhibition of NF-κB activation down-regulates TNF-α expression in AGE-BSA stimulated OA chondrocytes [ 16 ]. In the present study, EGCG was also found to be a potent inhibitor of the IL-1β-induced expression of IL-6 via inhibition of JNK-MAPK activation.

However, modulatory effects of EGCG on the IL-8 and TNF-α production appeared to be specifically via inhibition of NF-κB activation, as no role of JNK pathway was observed in the regulation of IL-8 and TNF-α expression using a specific inhibitor of JNK SP in IL-1β-stimulated OA chondrocytes. Inhibition of pMAPK SB was found to potently suppress the expression of IL-6, IL-8 and TNF-α in IL-1β-stimulated OA chondrocytes independent of NF-κB inhibition.

Taken together these results suggest that activation of pMAPK is responsible for the optimum expression of IL-6, IL-8 and TNF-α in IL-1β-stimulated OA chondrocytes, while JNK appeared to be critical for the expression of IL-6 but not for IL-8 and TNF-α in IL-1β-stimulated OA chondrocytes.

LIF is a cytokine whose expression is found to be high in OA cartilage and can be enhanced by IL-1β stimulation [ 38 , 39 ]. Interestingly, LIF is a potent suppressor of chondrocyte proteoglycan synthesis [ 40 ], induces collagenase 3 MMP [ 41 ], IL-1 and IL-6 expression [ 42 ] and up-regulates COX-2 and PGE 2 synthesis [ 43 ].

LIF also stimulates proteoglycan resorption and its inhibitors are considered to have a therapeutic potential for the treatment of RA [ 44 ].

To our knowledge, this report is the first demonstrating that EGCG significantly inhibits LIF mRNA and protein expression in IL-1β-stimulated OA chondrocytes. Thus, EGCG may be developed as a safe and effective inhibitor of LIF in OA. Colony stimulating factors CSF were among the first cytokines found in RA synovial fluid [ 45 ], and their increased expression was correlated with the severity of rheumatoid arthritis RA [ 46 ] and recently with OA pathogenesis [ 47 ].

There are numerous reports of GM-CSF precipitating or exacerbating established inflammatory disorders [ 48 ]. Moreover, antagonism of GM-CSF markedly reduces established disease in mouse models of RA and has a comparable effect to that of anti-TNF treatment [ 49 ].

Another new gene demonstrated in this report to be over-expressed in IL-1β-stimulated OA chondrocytes was IL Our results demonstrate for the first time that EGCG inhibits IL-1β-induced mRNA and protein expression of IL-7 and GMCSF in OA chondrocytes.

IL-7 is considered as a potential contributor to OA pathogenesis [ 50 ]. Although very little progress has been made in developing and testing anti-IL-7 therapy in animal models of OA, there is an increased interest in IL-7 as a potent stimulator of matrix metalloproteinase expression in OA [ 50 , 51 ].

In this study, we have also investigated the role of NF-κB and MAPKs on the EGCG mediated inhibition of LIF, GM-CSF and IL-7 in IL-1β-stimulated chondrocytes. Our study showed that EGCG inhibits the expression of LIF, GM-CSF and IL-7 via inhibition of NF-κB in IL-1β-stimulated OA chondrocytes.

Our results also point out that inhibition of JNK using specific inhibitor SP in the presence of IL-1β down-regulates LIF and IL-7 mRNA expression, suggesting the inhibition of JNK activation as an important event in the EGCG mediated down regulation of LIF and IL-7 expression in these cells.

In this study it was also discovered that GM-CSF expression was regulated by JNK, ERK and pMAPKs in OA chondrocytes in response to IL-1β. As EGCG did not inhibit ERK and pMAPK activation in IL-1β-stimulated OA chondrocytes, EGCG mediated down-regulation of GM-CSF expression may be mediated via NF-κB or by JNK-MAPK inhibition.

Chemokines are important regulators of chronic inflammation, typically orchestrating leucocyte migration and expression of chemokine receptor has been demonstrated in chondrocytes [ 52 ] and synovial cells [ 53 ].

They have been implicated in the pathophysiology of inflammatory diseases including OA [ 54 , 55 ]. Our data demonstrated that ENA, GRO, GRO-α, MCP-1 and 3, MIP-1β, MIP-3α, GCP-2 and NAP-2 were expressed and released into the medium upon stimulation with IL-1β.

Our data also showed that their induction and expression were suppressed by EGCG in IL-1β- stimulated OA chondrocytes. Secretion of IP was also up-regulated by IL-1β and inhibited by EGCG. EGCG alone treatment was also effective in down-regulating the basal level of expression of GRO, GRO-α, MCP-1 and MIP-1β in OA chondrocytes.

Consistent with the present findings, induction of chemokines has been previously described after stimulation of chondrocytes with IL-1 [ 56 , 57 ], but their suppression by EGCG has not been previously described in OA chondrocytes.

However, Ahmed et al. These results indicated that the chemokine blockade by EGCG might be a promising novel therapeutic strategy for RA and OA. Recently, administration of EGCG markedly diminished the severity of collagen induced arthritis, macrophage infiltration, and the amount of CCL2-synthesizing osteoblasts [ 59 ].

Further, EGCG has been reported to decrease MCP-1 mRNA and protein expression and its receptor CCR2 expression in THP-1 cells [ 60 ].

Chemokine signaling pathway molecules may be up-regulated in arthritis by mechanical injury [ 52 ]. In accordance with the results of other group, where they showed the role of NF-κB in EGCG mediated down regulation of chemokine production [ 58 ], down-regulation of ENA, GRO, GRO-α, MCP-1 and 3, MIP-1β, MIP-3α, GCP-2 and NAP-2 by EGCG in the present study may also be mediated through the inhibition of NF-κB.

Suppression of MAPKs activation has also been linked to anti-inflammatory activity; we, therefore, tested whether EGCG mediates its inhibitory effects on chemokine expression via inhibition of MAPKs and the role of this pathway in the regulation of these selected chemokines.

In the present study, pspecific, JNK-specific and ERK-specific inhibitors SB, SP, and PD reduced the expression of ENA, and GRO.

However, the expression of GRO-α, IP and GCP-2 was susceptible only to inhibition of pMAPK activation. Expression of MIP-1β and MCP-1 was dependent on the activation of p and JNK MAPKs while expression of MCP-3 was found to be regulated by the JNK and ERK-MAPKs.

The expression level of NAP-2 was only affected by JNK inhibition in IL-1β-stimulated OA chondrocytes. In summary, our study demonstrates that EGCG exerts differential inhibitory expression of inflammatory mediators in articular chondrocytes in the presence of IL-1β.

These inhibitory effects are mediated via inhibition of MAPKs and NF-κB pathways in OA chondrocytes. Our results also demonstrate that some chemokines require the activation of pMAPK for optimum expression.

The use of protein antibody array allowed the identification of several new target proteins of EGCG in OA chondrocytes. This provides novel insights into the anti-inflammatory potential of EGCG on IL-1β-induced inflammatory response.

Although, EGCG did not show direct stimulatory effect on the proteins associated with the cartilage anabolic response, it was found to be a surprisingly broad spectrum inhibitor of IL-1β-induced cartilage catabolic and inflammatory factors known to be associated with the pathogenesis of arthritis.

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In this study, we have also investigated the role of NF-κB and MAPKs on the EGCG mediated inhibition of LIF, GM-CSF and IL-7 in IL-1β-stimulated chondrocytes. Our study showed that EGCG inhibits the expression of LIF, GM-CSF and IL-7 via inhibition of NF-κB in IL-1β-stimulated OA chondrocytes.

Our results also point out that inhibition of JNK using specific inhibitor SP in the presence of IL-1β down-regulates LIF and IL-7 mRNA expression, suggesting the inhibition of JNK activation as an important event in the EGCG mediated down regulation of LIF and IL-7 expression in these cells.

In this study it was also discovered that GM-CSF expression was regulated by JNK, ERK and pMAPKs in OA chondrocytes in response to IL-1β. As EGCG did not inhibit ERK and pMAPK activation in IL-1β-stimulated OA chondrocytes, EGCG mediated down-regulation of GM-CSF expression may be mediated via NF-κB or by JNK-MAPK inhibition.

Chemokines are important regulators of chronic inflammation, typically orchestrating leucocyte migration and expression of chemokine receptor has been demonstrated in chondrocytes [ 52 ] and synovial cells [ 53 ]. They have been implicated in the pathophysiology of inflammatory diseases including OA [ 54 , 55 ].

Our data demonstrated that ENA, GRO, GRO-α, MCP-1 and 3, MIP-1β, MIP-3α, GCP-2 and NAP-2 were expressed and released into the medium upon stimulation with IL-1β. Our data also showed that their induction and expression were suppressed by EGCG in IL-1β- stimulated OA chondrocytes.

Secretion of IP was also up-regulated by IL-1β and inhibited by EGCG. EGCG alone treatment was also effective in down-regulating the basal level of expression of GRO, GRO-α, MCP-1 and MIP-1β in OA chondrocytes. Consistent with the present findings, induction of chemokines has been previously described after stimulation of chondrocytes with IL-1 [ 56 , 57 ], but their suppression by EGCG has not been previously described in OA chondrocytes.

However, Ahmed et al. These results indicated that the chemokine blockade by EGCG might be a promising novel therapeutic strategy for RA and OA.

Recently, administration of EGCG markedly diminished the severity of collagen induced arthritis, macrophage infiltration, and the amount of CCL2-synthesizing osteoblasts [ 59 ]. Further, EGCG has been reported to decrease MCP-1 mRNA and protein expression and its receptor CCR2 expression in THP-1 cells [ 60 ].

Chemokine signaling pathway molecules may be up-regulated in arthritis by mechanical injury [ 52 ]. In accordance with the results of other group, where they showed the role of NF-κB in EGCG mediated down regulation of chemokine production [ 58 ], down-regulation of ENA, GRO, GRO-α, MCP-1 and 3, MIP-1β, MIP-3α, GCP-2 and NAP-2 by EGCG in the present study may also be mediated through the inhibition of NF-κB.

Suppression of MAPKs activation has also been linked to anti-inflammatory activity; we, therefore, tested whether EGCG mediates its inhibitory effects on chemokine expression via inhibition of MAPKs and the role of this pathway in the regulation of these selected chemokines.

In the present study, pspecific, JNK-specific and ERK-specific inhibitors SB, SP, and PD reduced the expression of ENA, and GRO. However, the expression of GRO-α, IP and GCP-2 was susceptible only to inhibition of pMAPK activation.

Expression of MIP-1β and MCP-1 was dependent on the activation of p and JNK MAPKs while expression of MCP-3 was found to be regulated by the JNK and ERK-MAPKs.

The expression level of NAP-2 was only affected by JNK inhibition in IL-1β-stimulated OA chondrocytes. In summary, our study demonstrates that EGCG exerts differential inhibitory expression of inflammatory mediators in articular chondrocytes in the presence of IL-1β.

These inhibitory effects are mediated via inhibition of MAPKs and NF-κB pathways in OA chondrocytes. Our results also demonstrate that some chemokines require the activation of pMAPK for optimum expression. The use of protein antibody array allowed the identification of several new target proteins of EGCG in OA chondrocytes.

This provides novel insights into the anti-inflammatory potential of EGCG on IL-1β-induced inflammatory response. Although, EGCG did not show direct stimulatory effect on the proteins associated with the cartilage anabolic response, it was found to be a surprisingly broad spectrum inhibitor of IL-1β-induced cartilage catabolic and inflammatory factors known to be associated with the pathogenesis of arthritis.

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Melgarejo E, Medina MA, Sánchez-Jiménez F, Urdiales JL: Epigallocatechin gallate reduces human monocyte mobility and adhesion in vitro. Br J Pharmacol. Download references. Support from the MetroHealth Medical Center, Cleveland, Ohio is acknowledged and greatly appreciated.

We also thank Dr. Brendan Patterson Department of Orthopedics, MHMC for providing human OA cartilage samples. You can also search for this author in PubMed Google Scholar. Correspondence to Tariq M Haqqi.

NA carried out the experimental work, collection, interpretation and manuscript drafting. TMH conceived of the study and its design, coordinated the study, interpreted data and drafted the manuscript.

All authors have read and approved the final manuscript. Additional file 1: Effect of EGCG on nitrite production by human OA chondrocytes stimulated with IL-1β. b-e Represents cytokine-antibody arrays showing the effects of EGCG on the expression pattern of cytokines produced by human OA chondrocytes upon IL-1β-stimulation.

For the array layout and identification of cytokines please see additional file 2. TIFF 1 MB. Reprints and permissions. Ann Rheum Dis ; 67 : iii70—iii Xing B, Xin T, Hunter R, Bing G.

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Download references. The authors would also like to acknowledge the laboratory assistance of Krystina Cocco, Sarah Muse, Nicole Regna and David Fulbrook, in addition to Melissa Makris for flow cytometry.

Virginia College of Osteopathic Medicine, Blacksburg, VA, USA. Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.

Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA. Department of Mechanical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.

You can also search for this author in PubMed Google Scholar. Correspondence to Abigail Peairs. Reprints and permissions. Peairs, A. et al. Cell Mol Immunol 7 , — Download citation. Received : 21 September Revised : 08 December Accepted : 17 January Published : 08 February Issue Date : March Anyone you share the following link with will be able to read this content:.

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Clinical and Experimental Nephrology Skip to main content Thank you for visiting nature. Abstract Epigallocatechingallate EGCG , a bioactive component of green tea, has been reported to exert anti-inflammatory effects on immune cells.

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EGCG has long been studied as an anti-cancer agent. Most of our understanding of this compound comes from the oncologic literature. As the pathways of oncology and inflammation converge, new lessons can be taken from the cross discipline.

Many of the same cytokines, chemokines, and molecular signals influencing cancer cells to grow also stimulate immune cells. Chapter 3 first explores the role of EGCG as both a preventative as well as a therapeutic agent and its effect on the dextran sulfate sodium DSS mouse model of colitis.

The influence of EGCG on immune cell function is then explored in chapter 4. One novel approach in chapter 4 has to do with a focus on intestinal epithelial cells as agents of an immune response, and how EGCG impacts their function in that role.

Chapter 5 explores the impact of EGCG on bolstering barrier function, as this is an important aspect of inflammatory bowel disease that is often neglected when considering new approaches to treating IBD. Dryden, Jr. Electronic Theses and Dissertations.

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