Sun Young Yoon

Expression of ADAM33 Is a Novel Regulatory Mechanism in IL-18-Secreted Process in Gastric Cancer

IL-18 has recently been reported to play a critical role in tumor migration, invasion, and metastasis. Because IL-18 has various biological activities after its secretion as an 18 kDa mature form, the regulation of the IL-18 secretion process is an important step in tumor progression. This study investigated the implication of IL-18 in vascular endothelial growth factor (VEGF)-D-regulated migration, along with the role of the IL-18 secretion process. VEGF-D enhanced cell migration, which was then blocked by inhibiting IL-18. VEGF-D increased IL-18 expression and secretion, suggesting that IL-18 is a critical mediator for VEGF-D-enhanced migration. VEGF-D induced a disintegrin and metalloprotease 33 (ADAM33) expression, which has a metalloproteinase domain. VEGF-D-enhanced IL-18 secretion and cell migration were inhibited by ADAM33 knock-down. Moreover, cell proliferation was considerably reduced in ADAM33 small interfering RNA transfectants. In conclusion, ADAM33 has a key role in gastric cancer pathogenesis by up-regulating IL-18 secretion process, resulting in increased cell migration and proliferation.

Thymosin β4 expression correlates with lymph node metastasis through hypoxia inducible factor-α induction in breast cancer

Intratumoral hypoxia has been correlated with distant metastatic potential. Two hypoxia inducible factors (HIFs), HIF-1α and HIF-2α, are induced by hypoxia, and high expression of these proteins has been correlated to angiogenesis and distant metastasis. Thymosin β4 (Tβ4) is frequently highly expressed in cancer, and this overexpression correlates with malignant progression. The objective of this study was to investigate the clinical correlation of HIF-α with Tβ4 and the intracellular functional roles of Tβ4 on HIF-α activation. We examined HIF-1α, HIF-2α and Tβ4 expressions in clinical human breast carcinoma (n=70) by immunohistochemistry. We show that high expression of HIF-1α and HIF-2α strongly correlates with Tβ4 expression (P≤0.0001) and overexpression of Tβ4 correlates significantly with patients with lymph node metastasis (P<0.05) of human breast cancer. Additionally, we demonstrate that hypoxia up-regulates intracellular Tβ4 protein, which then affects HIF-α activity, which is the key in regulating VEGF expression. We confirmed that hypoxia-induced intracellular Tβ4 and HIF-α activities were reduced by interference of Tβ4 expression using Tβ4 shRNA lentivirus. Vascular epidermal growth factor (VEGF)-A, a well-recognized lymphangiogenic cytokine, was also down-regulated, but VEGF-C and VEGF-D expressions were not affected. These findings suggest that the overexpression of Tβ4 is strongly associated with HIF-1α and HIF-2α expression and is also clinicopathologically involved with lymph node metastatic potential of breast cancer through the modulation of HIF-αactivation and induction of VEGF-A. Ultimately, these results highlight Tβ4 as a potentially therapeutic target in malignant cancers.

Thymosin beta 4 enhances NK cell cytotoxicity mediated by ICAM-1

Thymosin beta 4 (T beta 4), which is the major G-actin sequestering protein, has been shown to have ubiquitous distribution and multiple biological activities. However, T beta 4s functions in relation to natural killer(NK) cells are still unknown. In this study, we show that synthetic T beta 4 peptide increases NK cell cytotoxicity mediated by intercellular adhesion molecule-1 (ICAM-1) through the secretion of cytolytic granules to target cells. This suggests that T beta 4 is a key activator of NK cell cytotoxicity.

Interleukin-18 induces transferrin expression in breast cancer cell line MCF-7

Interleukin-18 (IL-18) has recently been shown to have a pro-cancer effect in various cancers. Increased serum levels of both IL-18 and transferrin in cancer patients are correlated with its malignancy. However, the relationship between transferrin and IL-18 is not well understood. Here, we show that exogenous transferrin enhanced breast cancer cell proliferation and the proliferation rate was reduced when endogenous transferrin expression was inhibited by transferrin siRNA. The expression of endogenous transferrin was found to be regulated by IL-18. Furthermore, we found that the MAPK pathway is involved in IL-18-induced transferrin production. In conclusion, IL-18 is suggested as an inducer of endogenous transferrin expression in breast cancer cells.

Interleukin-18-mediated interferon-gamma secretion is regulated by thymosin beta 4 in human NK cells

Thymosin beta 4 (Tβ4) is the major G-actin sequestering molecule and is abundant in lymphoid tissues. However, it is not clear what regulates Tβ4 expression and what its function is on natural killer (NK) cells. We investigated whether interleukin-18 (IL-18) has a role in Tβ4 expression and if enhanced Tβ4 influences IL-18-mediated interferon-gamma (IFN-γ) secretion. In this study, recombinant human IL-18 (rhIL-18) enhanced the endogenous level of Tβ4 through p38MAPK and JNK signaling pathway in the human NK cell line, NK-92MI. Overexpression of endogeneous Tβ4 stimulated IFN-γ expression and secretion. Additionally, pretreatment with an inhibitor for Tβ4 decreased IL-18-enhanced IFN-γ secretion, and transfection with Tβ4-specific short hairpin RNA resulted in reduction of IFN-γ production in primary NK cells as well as in the human NK cell line. Taken together, these data indicated that Tβ4 is regulated by IL-18 and is involved in IL-18-enhanced IFN-γ secretion in NK cells.

Plaque type psoriasiform eruption following Kawasaki disease.

To the Editor: Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology. It is widely believed that KD is caused by bacterial toxins that act as superantigens, and evidence exists to implicate streptococcal and staphylococcal superantigens in the development of guttate psoriasis, atopic dermatitis, and Kawasaki disease (1). Guttate psoriasis is a distinctive acute form of psoriasis and closely associated with preceding bacterial infections (2). Some authorities have claimed that chronic plaque psoriasis may also be made worse by infection (3). Guttate psoriasis has been described in KD (1,4). However, this is the first report, to the best of our knowledge, of a plaque type psoriasiform eruption mimicking chronic plaque psoriasis in KD. A 2-year-old boy presented with fever, solitary cervical lympadenopathy, conjunctivitis, dry, red-fissured lips, acral erythema, and edema of 5 days, duration. Three days previously, amorphorous erythematous maculopatches on the trunk and limbs had developed. He had a history of atopic dermatitis. He was treated with a single high dose of intravenous immunoglobulin (IVIG; 2 g/kg) and aspirin (80 mg/kg daily) orally, with the impression of Kawasaki disease. The next day, his fever and the amorphrous skin lesion subsided. Four days after IVIG administration, multiple scaly erythematous plaques and papules appeared on his limbs and trunk (Fig. 1). Two weeks later, desquamation of the fingers and toes was evident but the scaly plaques persisted. A biopsy specimen revealed confluent parakeratosis with collections of neutrophils and marked elongated rete ridges, compatible with psoriasis (Fig. 2). He was treated with topical calcipotriol (Diavonex ) and resolved within 1 month. It is widely believed that KD is caused by immune activation as the result of a response to a superantigen. Also in the pathogenesis of psoriasis, supportive data have been found for the hypothesis that superantigens might be involved in both the induction and persistence of psoriasis through T-cell activation. Massive cytokine production by macrophages, keratinocytes or langerhans cells and activation of autoreactive T and B cells that express particular Vb regions are considered to be the developmental mechanism of KD and psoriasis by superantigens (5). The relationship between streptococcal tonsillitis and acute guttate psoriasis is well recognized, but its relationship to chronic forms of psoriasis is less established (3). Wardrop et al (3) suggested that streptococcal tonsillitis can exacerbate chronic guttate, small and large plaque psoriasis just as it initiates the acute guttate forms. (A)

The combination of DHEA, histamine, and insulin increases adipogenic differentiation and enhances tissue transplantation outcome in mice

Adipose stem cells (ASCs) are pluripotent cells that can generate pure fat tissue for regeneration. Differentiated adipose cells have been generated by a common inducer cocktail composed of dexamethasone, insulin, and isobutylmethylxanthine (DIM). The major drawbacks of adipose cells are their tendency to float on the culture media and their cost. To overcome some of these disadvantages, a new inducer cocktail that includes insulin, dehydroepiandrosterone, and histamine (DHIH) was tested. As a result, lipid accumulation was elevated more than twofold with DHIH than with DIM. Cell adhesion and viability, which are important factors for stable differentiation, were increased with DHIH and were proven through measurement of mRNA expression levels of adhesion marker genes, N‐cadherin and vascular cell adhesion molecule, as well as through an alamar blue assay. The expression of adipogenesis‐related genes, adiponectin, and glucose transporter type 4 lasted for a long time. To improve the efficiency of grafting, cell adhesion and neovascularization need to be increased. Neovascularization was observed around the transplanted adipose cells, which showed a higher number of vessel formation in DHIH than in DIM. The above results suggest that DHIH can produce pure differentiated adipose cells effectively and enhance their adhesion onto the target location when these differentiated adipose cells were applied as a clinical resource.