Interleukin 6 To Generate Inhibitors Of Pharmacological Studies

lnterleukin 6 is a cytokine with pleiotropic effects. Disregulated production of interleukin 6 has been shown to be associated with a variety of diseases. The attempt in seeking for effective interleukin 6 biosynthetic inhibitors and its receptor antagonists is not only a new direction in the field of drug investigation, but it will also bring us further insight into the pathogenous mechanism of interleukin 6 in the process of diseases with the exploration of the mechanism of action of interleukin 6 biosynthetic inhibitors.In light of these viewpoints, a bioassay involving the interleukin 6 dependent murine hybridoma B9 cell line was used to detect the levels of released and cell-associated inteleukin 6 in cultured mouse peritoneal macrophages stimulated with phorbol ester ( phorbol 12-mynstate 13-acetate, PMA ), calcium ionophores A₂₃₁₈₇, chemotactic peptide fMLP and lipopolysaccharide ( LPS ). PMA, A₂₃₁₈₇ and fMLP were shown to induce a dose-dependent increase of both released and cell-associated interleukin 6. whereas. LPS caused increase of interleukin 6 activity in supernatants of cultured peritoneal macrophages of mice. The effects of PMA and A₂₃₁₈₇ suggest that the pathways of protein kinase C and calcium are involved in the production and secretion of interleukin 6. The effects of fMLP and LPS provide evidence that they participated in the process of inflammation The difference between LPS and the other three stimulators in cell-associated interleukin 6 activity might suggest a different mechanism of action of biosynthesis of interleukin 6.The leukotrienes. including LTA₄, LTB₄, LTC₄, LTD₄, LTE₄ and LTF₄, are a series of metabolites of aracmdonic acid through the pathway of 5-lipoxygenase. It is now known that leukotrienes are important inflammatory mediators with redundant activity, which participate in the process of several immuno-inflammatory diseases. LTC₄ and LTD₄ belong to peptide leukotrienes whose biological activity are different from that of LTB₄ in the process of inflammation. The results show that LTB₄, LTC₄ and LTD₄ can enhance interleukin 6 production from cultured peritoneal macrophages of mice. This reveals that there is some common biological activity between peptide leukotrienes and LTB₄. The optmial concentrations of LTB₄, LTC₄ and LTD₄ were 1.45 × 10^-6, 6.9×10^-8 and 8.05×10^-8 mol·L^-1. respectively. The results suggest that the peptide leukotrienes may play important roles on interleukin 6 production in the local milieu of inflammation.FMLP is an artificially synthetic peptide which mimics the component of bacterial wall invoking inflammation of the host during the period of infection. With the advantage of being eliminated from samples by dialysis, fMLP was used as stimulator in the experiments of screening interleukin 6 biosynthetic inhibitors. The results indicate that isorhapotigenin and resveratrol, at the same concentration range from 5×10^-6 to 4×10^-5 mol·L^-1, inhibited...