• Biomolecules & Therapeutics
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• v.29 no.3
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• pp.342-351
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• 2021

Liver colonization is initiated through the interplay between tumor cells and adhesion molecules present in liver sinusoidal endothelial cells (LSECs). This crosstalk stimulates tumor COX-2 upregulation and PGE2 secretion. To elucidate the role of the LSEC intercellular adhesion molecule-1 (ICAM-1) in the prometastatic response exerted by tumor and stromal COX-2, we utilized celecoxib (CLX) as a COX-2 inhibitory agent. We analyzed the in vitro proliferative and secretory responses of murine C26 colorectal cancer (CRC) cells to soluble ICAM-1 (sICAM-1), cultured alone or with LSECs, and their effect on LSEC and hepatic stellate cell (HSC) migration and in vivo liver metastasis. CLX reduced sICAM-1-stimulated COX-2 activation and PGE2 secretion in C26 cells cultured alone or cocultured with LSECs. Moreover, CLX abrogated sICAM-1-induced C26 cell proliferation and C26 secretion of promigratory factors for LSECs and HSCs. Interestingly, CLX reduced the protumoral response of HSC, reducing their migratory potential when stimulated with C26 secretomes and impairing their secretion of chemotactic factors for LSECs and C26 cells and proliferative factors for C26 cells. In vivo, CLX abrogated the prometastatic ability of sICAM-1-activated C26 cells while reducing liver metastasis. COX-2 inhibition blocked the creation of a favorable tumor microenvironment (TME) by hindering the intratumoral recruitment of activated HSCs and macrophages in addition to the accumulation of fibrillar collagen. These results point to COX-2 being a key modulator of processes initiated by host ICAM-1 during tumor cell/LSEC/HSC crosstalk, leading to the creation of a prometastatic TME in the liver.

• Toxicological Research
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• v.25 no.4
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• pp.159-173
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• 2009

Nuclear factor erythroid derived 2-related factor-2 (Nrf2) is a master transcription regulator of antioxidant and cytoprotective proteins that mediate cellular defense against oxidative and inflammatory stresses. Disruption of cellular stress response by Nrf2 deficiency causes enhanced susceptibility to infection and related inflammatory diseases as a consequence of exacerbated immune-mediated hypersensitivity and autoimmunity. The cellular defense capacity potentiated by Nrf2 activation appears to balance the population of $CD4^+$ and $CD8^+$ of lymph node cells for proper innate immune responses. Nrf2 can negatively regulate the activation of pro-inflammatory signaling molecules such as p38 MAPK, NF-${\kappa}B$, and AP-1. Nrf2 subsequently functions to inhibit the production of pro-inflammatory mediators including cytokines, chemokines, cell adhesion molecules, matrix metalloproteinases, COX-2 and iNOS. Although not clearly elucidated, the antioxidative function of genes targeted by Nrf2 may cooperatively regulate the innate immune response and also repress the expression of pro-inflammatory mediators.

• Molecules and Cells
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• v.38 no.9
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• pp.821-828
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• 2015

Monocytes are the major inflammatory cells that infiltrate most solid tumors in humans. The interaction of tumor cells with infiltrating monocytes and their adhesion to these monocytes play a significant role in altering the tumor to become more aggressive. Recently, exposure to lipopolysaccharide (LPS) was suggested to promote cancer cell adhesion to monocytes; however, little is known about the details of the signaling mechanism involved in this process. In this study, we found that LPS up-regulates ICAM-1 expression in MDA-MB-231 breast cancer cells, which facilitates their adhesion to THP-1 monocytes. In addition, we analyzed the signaling mechanism underlying the up-regulation of ICAM-1 and found that the siRNA-mediated depletion of BLT2 markedly suppressed the LPS-induced expression of ICAM-1 in MDA-MB-231 cells and the subsequent adhesion of these cells to THP-1 monocytes. Moreover, we demonstrated that myeloid differentiation primary response gene 88 (MyD88) lies downstream of LPS/TLR4 and upstream of BLT2 and that this 'MyD88-BLT2' cascade mediates ERK activation and subsequent ICAM-1 expression, which is critical for the adhesion of MDA-MB-231 cells to THP-1 monocytes. Taken together, our results demonstrate for the first time that LPS up-regulates ICAM-1 expression in breast cancer cells via a MyD88-BLT2-ERK-linked signaling cascade, leading to the increased adhesion of breast cancer cells to monocytes.

• Development and Reproduction
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• v.17 no.4
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• pp.409-420
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• 2013

Human serum (HS) has been reported to induce aggregation of human eyelid adipose-derived stem cells (HEACs) during high-density culture in vitro. The present study focused on the role of cell adhesion molecules and gelatinases during HS-induced aggregation of HEACs. HS-induced aggregation occurred between 9-15 days of culture. Cells aggregated by HS medium (HS-agg) showed stronger expression of ${\alpha}2$, ${\alpha}2B$, ${\alpha}X$, and CEACAM1 genes compared to non-aggregated cells in HS medium (HS-ex) or in control FBS-cultured cells. HS-agg were distinctly labeled with antibodies against ${\alpha}2$, ${\alpha}2B$, and ${\alpha}X$ proteins. Western blot results demonstrated that the two integrin proteins were greatly expressed in HS-agg compared to HS-ex and control FBS-cultured cells. Treatment of HEACs with anti-integrin ${\alpha}2$ antibody during culture in HS medium delayed aggregation formation. HS-agg exhibited strong expression of MMP1 and MMP9 compared to HS-ex or FBS-cultured cells. Conditioned media from HS-culture showed remarkable increase of MMP9 gelatinolytic activity in comparison to those from FBS-culture. However, there was no change of TIMP mRNA expression in relation to the HS-induced aggregation. Based on these results, it is suggested that integrin ${\alpha}2$, ${\alpha}2B$, and ${\alpha}X$, and MMP9 might play an important role in the HS-induced aggregation of HEACs.

• Molecules and Cells
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• v.40 no.5
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• pp.355-362
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• 2017

The ${\beta}2$ integrins are cell surface transmembrane proteins regulating leukocyte functions, such as adhesion and migration. Two members of ${\beta}2$ integrin, ${\alpha}M{\beta}2$ and ${\alpha}X{\beta}2$, share the leukocyte distribution profile and integrin ${\alpha}X{\beta}2$ is involved in antigen presentation in dendritic cells and transendothelial migration of monocytes and macrophages to atherosclerotic lesions. ${\underline{R}}eceptor$ for ${\underline{a}}dvanced$ ${\underline{g}}lycation$ ${\underline{e}}nd$ ${\underline{p}}roducts$ (RAGE), a member of cell adhesion molecules, plays an important role in chronic inflammation and atherosclerosis. Although RAGE and ${\alpha}X{\beta}2$ play an important role in inflammatory response and the pathogenesis of atherosclerosis, the nature of their interaction and structure involved in the binding remain poorly defined. In this study, using I-domain as a ligand binding motif of ${\alpha}X{\beta}2$, we characterize the binding nature and the interacting moieties of ${\alpha}X$ I-domain and RAGE. Their binding requires divalent cations ($Mg^{2+}$ and $Mn^{2+}$) and shows an affinity on the sub-micro molar level: the dissociation constant of ${\alpha}X$ I-domains binding to RAGE being $0.49{\mu}M$. Furthermore, the ${\alpha}X$ I-domains recognize the V-domain, but not the C1 and C2-domains of RAGE. The acidic amino acid substitutions on the ligand binding site of ${\alpha}X$ I-domain significantly reduce the I-domain binding activity to soluble RAGE and the alanine substitutions of basic amino acids on the flat surface of the V-domain prevent the V-domain binding to ${\alpha}X$ I-domain. In conclusion, the main mechanism of ${\alpha}X$ I-domain binding to RAGE is a charge interaction, in which the acidic moieties of ${\alpha}X$ I-domains, including E244, and D249, recognize the basic residues on the RAGE V-domain encompassing K39, K43, K44, R104, and K107.

• Journal of Life Science
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• v.31 no.9
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• pp.856-861
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• 2021

CD82/KAI1, identified as a metastasis suppressor, was initially known only as a molecular facilitator, but its various functions have recently been revealed. CD82 plays an important role in the stem-progenitor cell, angiogenesis, and muscle. We would like to introduce the recently reported functions and roles of CD82 in this review. CD82 is a member of the tetraspanin family, which consists of four transmembrane domains. The interaction between CD82 and cell adhesion molecules suppresses the metastasis of cancer. CD82 regulates the cell cycle of stem-progenitor cells in the stem cell niche. In the bone marrow, CD82 is expressed on long-term repopulating hematopoietic stem cells (LT-HSCs), which show multipotent differentiation potential. The interaction between CD82 and Duffy antigen receptor for chemokines (DARC) induces quiescence in LT-HSCs. CD82 also regulates Rac1 activity, resulting in the homing and engraftment of HSCs into the bone marrow niche. Besides, CD82 maintains the differentiation potential of muscle stem cells and prevents angiogenesis by inhibiting the expression of cytokines, such as IL-6 and VEGF and adhesion molecules in endothelial cells. CD82 is a key membrane protein that distinguishes the hierarchy of stem-progenitor cells, and is also important for amplification and verification of cellular resources. Further studies on the function of CD82 in various organs and cells are expected to advance cell biology and cell therapy.

• The Journal of Korean Physical Therapy
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• v.12 no.3
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• pp.415-432
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• 2000

In mammals. axotomy of peripheral nerve leads to a complex. These events include swelling of cell body, disappearance of Nissl substance. Proximal and distal axon undergoes a variable deriable degree of traumatic degeneration and wallerian degeneration, respectively. Nerve injury may result in cell death or regeneration. Molecular changes include proliferation of Schwann cells, upregulation of neurotropism, neural cell adhesion molecules and cytokine. Also growth cone plays an essential role in axon guidance through interaction of cytoskeleton. We review cellular and molecular events after nerve injury and describe nerve regeneration and associated proteins.

• BMB Reports
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• v.48 no.9
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• pp.495-500
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• 2015

Up-regulation of cell adhesion molecules and proinflammatory cytokines contributes to enhanced monocyte adhesiveness and infiltration into the skin, during the pathogenesis of various inflammatory skin diseases, including atopic dermatitis. In this study, we examined the anti-inflammatory effects of butein, a tetrahydroxychalcone, and its action mechanisms using TNF-α-stimulated keratinocytes. Butein significantly inhibited TNF-α-induced ICAM-I expression and monocyte adhesion in human keratinocyte cell line HaCaT. Butein also decreased TNF-α-induced pro-inflammatory mediators, such as IL-6, IP-10 and MCP-1, in HaCaT cells. Butein decreased TNF-α-induced ROS generation in a dose-dependent manner in HaCaT cells. In addition, treatment of HaCaT cells with butein suppressed TNF-α-induced MAPK activation. Furthermore, butein suppressed TNF-α-induced NF-kappaB activation. Overall, our results indicate that butein has immunomodulatory activities by inhibiting expression of proinflammatory mediators in keratinocytes. Therefore, butein may be used as a therapeutic agent for the treatment of inflammatory skin diseases. [BMB Reports 2015; 48(9): 495-500]

• Bulletin of the Korean Chemical Society
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• v.31 no.1
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• pp.64-68
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• 2010

Four quinolone alkaloids were isolated by bioactivity-guided fractionation from the methanol extracts of Evodiae fructus fruits. Structures of compounds were elucidated by spectroscopic analysis ($^1H$-, $^{13}$C-NMR and MS), as follows: 1-methyl-2-undecyl-4(1H)-quinolone (1), evocarpine (2), dihydroevocarpine (3) and mixture of [1-methyl-2-[(Z)-10-pentadecenyl]-4(1H)-quinolone and 1-methyl-2-[(Z)-6-pentadecenyl]-4(1H)-quinolone] (4). They inhibited the interaction of sICAM-1 and LFA-1 in THP-1 cells at $IC_{50}$ values of >150 (1), 109.8 (2), >150 (3) and $40.9 {\mu}M$ (4), respectively,

• Archives of Pharmacal Research
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• v.27 no.10
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• pp.1073-1079
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• 2004

Interactions of the cell adhesion molecules are known to play important roles in mediating inflammation. The proinflammatory cytokine, tumor necrosis factor-${\alpha}$(TNF-${\alpha}$), activates the NF-kB signaling pathway, which induces the expression of various genes, such as intercellular adhesion molecule-1 (ICAM-1). In this study, the effect of vitamin C on the ICAM-1 expression induced by TNF-${\alpha}$ in a human neuroblastoma cell line, SK-N-SH was investigated. Treatment with vitamin C resulted in the downregulation of the TNF-${\alpha}$-induced surface expression and ICAM-1 mRNA levels in a concentration-dependent manner. Moreover, a gel shift analysis indicated that vitamin C dose-dependently inhibited the NF-kB activation and IkB${\alpha}$ degradation induced by TNF-${\alpha}$. Taken together, these results suggest that vitamin C downregulates TNF-${\alpha}$- induced ICAM-1 expression via the inhibition of NF-kB activation.