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Oxidative stress mediates chemical hypoxia-induced injury and inflammation by activating NF-?b-COX-2 pathway in HaCaT cells.

ABSTRACT: Hypoxia of skin is an important physiopathological process in many diseases, such as pressure ulcer, diabetic ulcer, and varicose ulcer. Although cellular injury and inflammation have been involved in hypoxia-induced dermatic injury, the underlying mechanisms remain largely unknown. This study was conducted to investigate the effects of cobalt chloride (CoCl(2)), a hypoxia-mimicking agent, on human skin keratinocytes (HaCaT cells) and to explore the possible molecular mechanisms. Exposure of HaCaT cells to CoCl(2) reduced cell viability and caused overproduction of reactive oxygen species (ROS) and oversecretion of interleukin-6 (IL-6) and interleukin-8 (IL-8). Importantly, CoCl(2) exposure elicited overexpression of cyclooxygenase-2 (COX-2) and phosphorylation of nuclear factor-kappa B (NF-?B) p65 subunit. Inhibition of COX-2 by NS-398, a selective inhibitor of COX-2, significantly repressed the cytotoxicity, as well as secretion of IL-6 and IL-8 induced by CoCl(2). Inhibition of NF-?B by PDTC (a selective inhibitor of NF-?B) or genetic silencing of p65 by RNAi (Si-p65), attenuated not only the cytotoxicity and secretion of IL-6 and IL-8, but also overexpression of COX-2 in CoCl(2)-treated HaCaT cells. Neutralizing anti-IL-6 or anti-IL-8 antibody statistically alleviated CoCl(2)-induced cytotoxicity in HaCaT cells. N-acetyl-L-cysteine (NAC), a well characterized ROS scavenger, obviously suppressed CoCl(2)-induced cytotoxicity in HaCaT cells, as well as secretion of IL-6 and IL-8. Additionally, NAC also repressed overexpression of COX-2 and phosphorylation of NF- B ? p65 subunit induced by CoCl(2) in HaCaT cells. In conclusion, our results demonstrated that oxidative stress mediates chemical hypoxia-induced injury and inflammatory response through activation of NF-?B-COX-2 pathway in HaCaT cells.

SUBMITTER: Yang C

PROVIDER: S-EPMC3887613 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Oxidative stress mediates chemical hypoxia-induced injury and inflammation by activating NF-κb-COX-2 pathway in HaCaT cells.

Yang Chuntao C Ling Hongzhong H Zhang Meifen M Yang Zhanli Z Wang Xiuyu X Zeng Fanqin F Wang Chuhuai C Feng Jianqiang J

Molecules and cells 20110420 6

Hypoxia of skin is an important physiopathological process in many diseases, such as pressure ulcer, diabetic ulcer, and varicose ulcer. Although cellular injury and inflammation have been involved in hypoxia-induced dermatic injury, the underlying mechanisms remain largely unknown. This study was conducted to investigate the effects of cobalt chloride (CoCl(2)), a hypoxia-mimicking agent, on human skin keratinocytes (HaCaT cells) and to explore the possible molecular mechanisms. Exposure of HaC ...[more]

PMID: 21533553

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Project description:Scientific evidence attests that the epidermis receives excessive ultraviolet B (UVB) radiation, triggering the generation of substantial quantities of reactive oxygen species (ROS), which disrupted the delicate equilibrium of oxidation-reduction, leading to oxidative stress and inflammation. The historical use of honeysuckle polyphenols (HPs) has garnered our attention due to their efficacy in inhibiting oxidative damage. In this study, HPs were prepared from honeysuckle flowers employing an ultrasonic-assisted extraction method and quantitatively analyzed by a LC-MS/MS, and the mechanisms underlying HPs' antioxidative and anti-inflammatory effects on a UVB-irradiated HaCaT cell model were systematically investigated. The results showed that HPs had a significant cellular repair effect on UVB-irradiated HaCaT cells (p < 0.001). The mechanism of action indicated that HPs could allow Nrf2 to enter the nucleus by regulating the dissociation of Nrf2 from Keap1, which further increases the activity of downstream proteases (SOD and CAT), increases ROS scavenging, and reduces the intracellular malondialdehyde (MDA) level. In addition, HPs could down-regulate Toll-like receptor 4 (TLR4) and inhibit NF-κB (P65) dissociating from IκBα, resulting in a decrease in NF-κB (P65) entry into the nucleus and a decrease in inflammatory factors (TNF-α, IL-6, and IL-1β). In addition, four key compounds in HPs, including chlorogenic acid, quercetin, isorhamnetin, and luteolin, were selected to verify the mechanism of HPs repairing UVB damage using molecular docking techniques. The experiment suggested that four key active compounds could effectively occupy the Kelch homologue (Kelch) structural domain of Keap1, competitively bind with Nrf2, and facilitate the promotion of Nrf2 binding, ultimately enhancing the translocation of Nrf2 into the nucleus. In addition, four key active compounds could effectively interact with NF-κB (P65) through hydrogen bonding, van der Waals forces, and electrostatic forces to inhibit its entry into the nucleus. In summary, HPs can effectively repair the damage of HaCaT cells by UVB radiation and can be used to develop health and cosmetic products for the treatment of UV radiation-induced diseases.

Dataset Information

Oxidative stress mediates chemical hypoxia-induced injury and inflammation by activating NF-?b-COX-2 pathway in HaCaT cells.

Publications

Oxidative stress mediates chemical hypoxia-induced injury and inflammation by activating NF-κb-COX-2 pathway in HaCaT cells.

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