Pharmacological Inhibition Of ERK Research Articles

Lipopolysaccharide-induced transcriptional activation of interleukin-10 is mediated by MAPK- and NF-κB-induced CCAAT/enhancer-binding protein δ in mouse macrophages

We have previously revealed that LPS can activate transcription of the IL-10 gene promoter through transcription factors Sp1, C/EBPβ and C/EBPδ in mouse macrophages. In this study, we determined that NF-κB and MAPK signal pathways, including ERK, JNK, and p38, were all involved in LPS-induced IL-10 gene expression. Treatment of cells with the pharmacological inhibitors of ERK, JNK, p38 and NF-κB respectively inhibited LPS-induced IL-10 protein expression in a dose-dependent manner. These inhibitors also decreased the LPS-induced IL-10 mRNA expression at a high concentration used. With transient overexpression of the IκB expression plasmids, or the dominant negative plasmids of ERK2, JNK, p38 together with reporter vector containing IL-10 promoter region, all four expression plasmids inhibited LPS-induced IL-10 promoter activity individually. It is known that the increase in protein and DNA binding of C/EBPβ and δ could activate IL-10 gene expression. In this study, we also identified that all four pharmacological inhibitors inhibited the protein expression of C/EBPδ individually, but not C/EBPβ. In the presence of all three MAPK inhibitors, or only NF-κB inhibitor, LPS-induced protein expression and DNA binding of C/EBPδ were completely inhibited simultaneously, and LPS-induced expression of IL-10 protein and mRNA was also inhibited totally. Taken together, these results suggested that LPS-induced IL-10 expression was mediated at least through the pathway of NF-κB- and MAPK-induced protein expression and DNA binding of C/EBPδ.

Pulmonary and activation-regulated chemokine stimulates collagen production in lung fibroblasts.

Levels of pulmonary and activation-regulated chemokine (PARC) mRNA and protein are increased in the lungs of patients with pulmonary fibrosis. The purpose of this study was to establish whether PARC could be directly involved in development of pulmonary fibrosis by stimulating collagen production in lung fibroblasts. Exposure to PARC increased production of collagen mRNA and protein by 3- to 4-fold in normal adult lung and dermal fibroblast cells. Collagen mRNA transiently increased after 3-6 h of activation with PARC, with an increase in collagen protein detected after 24 h of activation. At the same time, PARC had less pronounced effect on fibroblast proliferation, not exceeding 50% increase over control nonstimulated cells. PARC intracellular signaling led to activation of ERK1/2, but not p38, in fibroblasts; pharmacologic inhibition of ERK, but not p38, also blocked PARC's effect on collagen production. Inhibition experiments with pertussis toxin suggested that PARC receptor is G protein-coupled. Thus, PARC is a member of the CC chemokine family that acts directly as a profibrotic factor.

Dose effect of oxidative stress on signal transduction in aging

Reactive oxygen species (ROS) during normal metabolism signal cells to stimulate proliferation or to cause cellular damages, depending on a specific concentration. Energy restriction (ER) increases life span in animals, which can explain an effective modulator for reducing oxidative stress. Oxidative stress can result from a decrease in the protection against ROS. The deleterious effects of oxidative stress generally occur after exposure to a relatively high concentration of ROS. Alternatively, it has been suggested that a low concentration of ROS can exert important physiological roles in cellular signaling and proliferation. Signal pathways are crucial for cell survival or death. It is generally acceptable that aged cells have less response to stresses such as ROS than young cells. Oxidative stresses induce JNK and p38 kinase pathways regulated by redox regulatory proteins: thioredoxin and glutathione s-transferase, respectively. Antioxidants such as selenium block apoptosis induced by ROS through blocking apoptotic signal ASK1 and stimulating survival signal Akt activity. Old hepatocytes are more susceptible to ROS-induced apoptosis than young hepatocytes, which is associated with low expression of ERK and Akt kinases. Pharmacological inhibition of ERK and Akt activation in the young cells markedly increase their sensitivity to H 2O 2, and ER, by preventing loss of ERK and Akt activities, enhances survival of old hepatocytes to a level similar to those of young cells. Expressions of signal pathways such as survival and apoptotic signals can regulate cells’ fate and aging process. Further studies on the interaction of signal pathways may change the scientific direction of the study of aging.