Studies on the suppressive factor from parasite of NO synthase and cytokine gene expression in macrophages

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We found that excretory/secretory (ES) products of Spirometra erinaceieuropaei suppress the gene expression of iNOS, TNF-α, chemokines in mouse peritoneal macrophages stimulated with LPS.We examined the suppesive mechanism of gene expression in the present investigation.(1) The TNF-α gene expression was suppressed by ES products downstream of TLR4 based on the comparison of the effect of ES products in C3H/HeN miceand C3H/HeJ mice, in which point mutation was observed in TLR4.(2) These suppressive effects were not related with prostaglandin E2, IL-10 and secretory leukocyte protease inhibitor (SLPI) , which are produced in macrophages and suppress the macrophage functions.(3) The stability of TNF-αmRNA was not reduced by the treatment of ES products.(4) The translocation of NF-κB to nucleus and NF-κB binding activity to κB element was not reduced by the treatment of ES products.(5) In J774.1 and RAW 264.7 cell line macrophages, nitric oxide production and gene expression of IP-10 and TNF-α were suppressed. Then, we found that these cell lines are useful in the studies of suppressive mechanism.(6) ES inhibited the phospho-p38 MAP kinase and phospho-ERK as well as MAPK inhibitors, SB 203580 and PD 98059, respectively. We supposed that this is one of the suppressive mechanism of gene expression.(7) The suppressive effect of ES products almost diminished by the treatment with trypsin 15 μg/ml or protease K0.1U/ml. Judging from these data, the supressive factor is supposed to be a protein.