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Lee, Sukmook,Chung, Junho,Ha, In Su,Yi, Kyesook,Lee, Ji Eun,Kang, Hee Gyung,Choi, Inho,Oh, Kook-Hwan,Kim, Jae Young,Surh, Charles D,Ahn, Curie Oxford University Press 2007 International immunology Vol.19 No.12
<P>Although a severe shortage of organs in transplantation can be overcome by using xenotransplantation of porcine donor organs, profound immune rejection to xenogeneic antigens remains a main obstacle. To elucidate the role of hydrogen peroxide (H(2)O(2)) on xenogeneic immune responses, we investigated its effects on porcine aortic endothelial cells (PAECs). We found that H(2)O(2) can specifically induce vascular cell adhesion molecule-1 (VCAM-1) expression on PAECs, but little on human umbilical vein endothelial cells (HUVECs) and aortic endothelial cells (HAECs). Furthermore, we further confirmed that H(2)O(2) induces activation of NFkappaB in PAECs, but not in HAECs. Interestingly, cell adhesion assay showed that U937, human promonocytic leukocyte, can adhere to PAECs in an H(2)O(2)-dependent manner and by using a neutralizing assay with anti-VCAM-1-specific antibodies, we also found that the interaction is mediated primarily by VCAM-1. Finally, we also demonstrated that up-regulation of VCAM-1 expression on PAECs by reactive oxygen species-producing HL-60, human leukemic neutrophil cells, could be significantly diminished by over-expressing an H(2)O(2)-removing catalase. In summary, our results suggest that NFkappaB-dependent porcine VCAM-1 expression by H(2)O(2) may promote interaction of human leukocyte to PAECs, and thus may play an important role on inducing xenogeneic immune responses.</P>
Lee, Sukmook,Yoon, Il-Hee,Yoon, Aerin,Cook-Mills, Joan M,Park, Chung-Gyu,Chung, Junho American Association of Immunologists 2012 Journal of Immunology Vol. No.
<P>VCAM-1 plays a key role in leukocyte trafficking during inflammatory responses. However, molecular mechanisms underlying this function have not been clearly elucidated. In this study, using phage display technology, we developed a rabbit/human chimeric VCAM-1 Ab, termed VCAM-1 domain 6 (VCAM-1-D6), which specifically recognizes aa 511-599 within the sixth Ig-like domain. We report that the VCAM-1-D6 Ab blocked U937 cell transmigration across activated HUVECs but did not alter adhesion of U937 cells to the HUVECs. We also demonstrate that VCAM-1-D6 does not alter TNF-α-stimulated endothelial cell chemokine or cytokine production. Furthermore, through in vivo efficacy testing using a mouse islet allograft model, we demonstrate that VCAM-1-D6 significantly alleviates allograft rejection by blocking leukocyte infiltration to the grafted islets. Taken together, our results suggest that the VCAM-1-D6 Ab may block VCAM-1-mediated inflammation and could be a useful tool in treating inflammatory diseases.</P>
Weak response of porcine C5a receptor towards human C5a in miniature pig endothelial cells and PMNs
Yi, Kye Sook,Lee, Sukmook,Kang, Yoon-Ho,Bae, Yoe-Sik,Hwang, Seung Yong,Ha, Insu,Kim, Hyori,Kim, Min Soo,Cho, Bumrae,Kang, Hee Jung,Bang, Ki Tae,Kim, Jae Yong,Yang, Jaeseok,Chung, Junho,Ahn, Curie Blackwell Publishing Ltd 2007 Xenotransplantation Vol.14 No.6
<P>Abstract: Background: </P><P>The anaphylatoxin C5a is a potent inflammatory molecule generated during complement activation. Although some reports have implicated C5a in xenograft rejection, to date, the molecular compatibility between human C5a and porcine C5a receptor (C5aR) has been little studied. To examine the need for pC5aR-deficient pig in xenotransplantaion, we aimed to look at the degree of direct interaction between human C5a (recipient side) and porcine endothelial cells (PECs) and porcine polymorphonuclear neutrophils (PMNs) (donor side).</P><P>Methods: </P><P>Following the treatment of human C5a to isolated porcine PMNs, transmigration of PMNs was measured by Transwell system and superoxide generation by cytochrome <I>c</I> reduction assay. Next, the effects of human C5a on several intracellular signaling pathways were further checked; actin cytoskeletal change was observed under a confocal microscope after staining with Alexa Fluor-546-phalloidin, intracellular calcium mobilization was measured by spectrofluorophotometer. The degree of direct effect of human C5a on porcine PMNs was compared with that in human PMNs. Finally, microarray was performed to monitor the effect of human C5a on gene expression of PEC and the expression of several candidate proteins was checked by flow cytometry.</P><P>Results: </P><P>We found that human C5a was able to induce chemotaxis, superoxide generation, actin cytoskeletal change, and intracellular calcium mobilization in porcine PMNs. However, higher concentration of human C5a was required to stimulate porcine PMNs in comparison with activating human PMNs. The amino acid sequences of porcine C5aR with those of human C5aR showed a sequence homology of only 67%. To elucidate the effect of human C5a to PECs, microarray analysis following the treatment of PECs with human C5a was performed. These data showed that human C5a did not significantly affect gene transcription patterns in PECs. Additionally, treatment of PECs with human C5a also did not induce protein expression of several cell adhesion molecules, including vascular cell adhesion molecule-1, intercellular adhesion molecule-1, P-selectin, and E-selectin, or secretion of interleukin-8 from PECs.</P><P>Conclusions: </P><P>These results suggest that human C5a may play a minor role on PEC activation possibly due to molecular incompatibility across the species barrier.</P>
Kang, Dong Il,Lee, Sukmook,Lee, Jung Tae,Sung, Byung Je,Yoon, Ji-Yong,Kim, Jin-Ki,Chung, Junho,Lim, Soo-Jeong Informa UK, Ltd. 2011 Journal of microencapsulation Vol.28 No.3
<P>When an inflammatory stimulus is given, vascular endothelial cells express various cell adhesion molecules including the vascular cell adhesion molecule (VCAM)-1. In this study, the possibility of specifically delivering anti-inflammatory drugs to activated endothelial cells by utilizing VCAM-1 as a target receptor was explored by loading celecoxib, a selective cyclooxygenase-2 inhibitor, into liposomes coupled to the Fab′??fragment against VCAM-1. Anti-VCAM-1-Fab′??conjugated liposomes were prepared by forming an amide linkage between amino groups of Fab′??and the carboxylic group of glutaryl-<I>N</I>-phosphatidylethanolamine in liposomes using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide as a cross-linker in the presence of sulpho-<I>N</I>-hydroxysuccinimide. The coupling of Fab′??to phospholipids constituting liposomes was confirmed by SDS-PAGE analysis. Under our optimized conjugation conditions, 130.0 ??µ쨉g Fab′??was coupled to 1 ??µ쨉mol liposomes. Immunoblotting analysis showed that VCAM-1 protein expression could be induced by incubating human umbilical vein endothelial cells (HUVEC) with TNF-α慣. Confocal laser microsopy analysis revealed that Fab′??conjugation to liposomes selectively increased liposomal uptake in TNF-α慣-pre-stimulated (VCAM-1-expressed) HUVECs, but not in cells without VCAM-1 expression. The concentration of celecoxib loaded in Fab′??conjugated liposomes was 281.1 ??±짹 ??29 ??µ쨉g/mL, suggesting that liposomal loading also helped to overcome the limitations in celecoxib administration caused by its poor water solubility. Celecoxib loaded in Fab′??conjugated liposomes inhibited prostaglandin E<SUB>2</SUB> (PGE<SUB>2</SUB>) production induced by TNF-α慣-pre-stimulation more efficiently than when loaded in conventional liposomes. Therefore, Fab′??conjugated liposomes served as a drug delivery system with dual functions: targeted delivery and solubilizing capacity.</P>
Kim, Ji-Eun,Lee, Sukmook,Han, Kyou-Sup,Kim, Hyun Kyung Lippincott Williams Wilkins, Inc. 2011 Blood coagulation & fibrinolysis Vol.22 No.2
Activation of the vascular endothelium and increased adhesion of circulating leukocytes to the activated endothelium are important events in inflammation and coagulation. Aurintricarboxylic acid (ATA), a triphenylmethyl dye compound, is known to inhibit platelet adhesion by interfering with the binding of von Willebrand factor to platelet glycoprotein Ib. However, the effect of ATA on the inflammatory response of endothelial cells has not yet been investigated. Here, we investigated the functional role and molecular mechanism of ATA on the activation of human endothelial cells. ATA inhibited the expression of intercellular adhesion molecule-1 (ICAM-1), and endothelial cell selectin (E-selectin) was upregulated on human umbilical vein endothelial cells (HUVECs) in response to tumor necrosis factor-α or lipopolysaccharide (LPS). We also observed the inhibitory effect of ATA on LPS-induced mRNA expression of ICAM-1 and E-selectin. Furthermore, ATA inhibited the binding of leukocytes to activated HUVECs. ATA significantly inhibited the nuclear translocation of nuclear factor-&kgr;B (NF-&kgr;B) and degradation of I&kgr;B on activated HUVECs, suggesting that ATA inhibits NF-&kgr;B signaling. Finally, three NF-&kgr;B inhibitors effectively inhibited the expressions of ICAM-1 and E-selectin on activated endothelial cells. The present data suggest that ATA exerts beneficial effect in various inflammation conditions through inhibition of adhesion molecule expression in activated endothelial cells and the resulting inhibition of leukocytes tissue accumulation.