Helminth Infections Prevent Autoimmune Diseases through Th2-Type Immune Response

Helminth parasites are known to elicit the immune response towards T helper 2 (Th2)-type, characterized by Th2 related cytokines, that typically include interleukin-4 (IL-4), IL-5 and IL-13. In this review we will describe the mechanisms involved in helminth induced Th2 immune response. Intestinal epithelial cells (IECs) produce thymic stromal lymphopoietin (TSLP), which is both necessary and sufficient for the initiation of Th2 cytokine-driven inflammation. IL-33 mRNA is expressed early during parasite infection and IL-33 binds ST2 receptor, both of which are associated with optimal CD4+ Th2 polarization. Following innate immune cell recognition, basophils and mast cell can secrete Th2 type cytokines that are thought to contribute to CD4+ Th2 differentiation. Additionaly, dendritic cell conditioned with some helminth products can promote CD4+ Th2 differentiation. Alternatively activated macrophages, activated by the Th2 cytokines IL-4 and IL-13 in parasitic infections, contribute to the host protective response: control of Th1-type inflammation, wound healing and worm expulsion. Experimentally, helminths have been associated with protection against a number of autoimmune disorders, including inflammatory bowel diseases and type 1 diabetes. It may be a novel strategy to ameliorate autoimmune inflammation by expanding and activating the Th2 response originated from parasites

Regulation of TNF-α, IL-1β and ICAM-1 Gene Expression in THP-1 Monocytes Stimulated with Plasmodium falciparum-Cultured Medium by Excretory/Secretory Products from Spirometra erinaceieuropaei Plerocercoids

We have reported that excretory/secretory (ES) products from Spirometra erinaceieuropaei plerocercoids suppress production and gene expression of tumor necrosis factor (TNF)-α in murine macrophages stimulated with lipopolysaccharide. The present study demonstrates that ES products suppress TNF-α, interleukin (IL)-1β and intercellular adhesion molecule (ICAM)-1 gene expression in human monocytic leukemia cell line THP-1 stimulated with Plasmodium falciparum-cultured medium (Pf-CM). Inhibition of extracellular-signal regulated protein kinase 1/2 (ERK1/2) with PD98059 reduced TNF-α, IL-1β and ICAM-1 gene expression; on the contrary inhibition of p38 mitogen-activated protein kinase (MAPK) with SB203580 increased the expression of these genes. These findings indicated that ERK1/2, but not p38 MAPK pathway is important for induction of TNF-α, IL-1β and ICAM-1 gene expression in Pf-CM stimulated THP-1 monocytes. ES products additionally suppress IL-1β, but not TNF-α and ICAM-1 gene expression in Pf-CM stimulated THP-1 cells treated with PD98059. We hypothesize that ES products may be useful in reducing falciparum malaria-induced inflammatory response and sequestration in the late stage of malarial diseases such as cerebral malaria

Suppression of Chemokine Gene Expression and Production in LPS-Stimulated Macrophages by a 130 kDa Glycoprotein from Plerocercoids of Spirometra erinaceieuropaei

Previous studies have shown that excretory/secretory (ES) products from plerocercoids of Spirometra erinaceieuropaei have immunosuppressive activities. We report here that a 130 kDa glycoprotein (ES130) purified from ES products as a suppressive factor of nitric oxide synthesis in LPS-stimulated RAW 264.7 cells inhibited the gene expression of 3 chemokines, regulated on activation normal T cell expressed and secreted (CCL5/RANTES), macrophage inflammatory protein 2 (CXCL2/MIP-2), interferon-inducible protein 10 kDa (CXCL10/IP-10) in RAW 264.7 cells and mouse peritoneal macrophages stimulated with LPS for 3 h. These chemokines are important factors for recruitment of inflammatory leukocytes. RANTES acts on monocytes, basophils, lymphocytes, natural killer cells and eosinophils. MIP-2 is a potent chemoattactant for neutrophils, while IP-10 binds to Th1 cells. Nearly 80% of MIP-2 gene expression and 50% of IP-10 gene ex-pression in peritoneal macrophages stimulated with LPS for 8 h was suppressed as well as these chemokine production by the preincubation with 100 ng/mL of ES130 or 5000 ng/mL crude ES products for 24 h. On the other hand the mRNA expression of RANTES in macrophages stimulated with LPS for 8 h or 24 h was not inhibited by ES130 or crude ES products, while the RANTES chemokine levels in the incubation medium were significantly suppressed. These results suggest that ES130 may attenuate inflammation around the plerocercoids by inhibiting these chemokine production

Suppression of LPS-induced Cyclooxygenase-2 (cox-2) Gene Expression in Mouse Macrophages by Excretory/Secretory Products of Spirometra erinaceieuropaei Plerocercoids

The escape mechanism of parasites from inflammatory processes has been thought to be one of the most important tools for their survival in infected tissues. On the other hand, inducible cyclooxygenase-2 (cox-2) has been shown to play a major role in the process of inflammation. We investigated the effect of excretory/secretory (ES) products from the plerocercoids of Spirometra erinaceieuropaei on cox-2 gene expression in a murine macrophage cell line (RAW 264.7). Preincubation of the macrophages with the ES products inhibited LPS-induced cox-2 mRNA expression by 75% as well as its protein production. Dibutyryl cAMP enhances LPS-induced cox-2 mRNA expression. The ES products also inhibited this enhanced expression by 46%. Inhibition of p38 mitogen-activated protein kinase (MAPK) with SB203580 or that of extracellular signal-regulated protein kinase with PD98059 reduced LPS-induced cox-2 mRNA expression by 75% or 52%, respectively, along with its protein production. This evidence suggests that both MAPK pathways are crucial for full induction of cox-2 gene expression. One experiment using a transcriptional inhibitor, actinomycin-D, showed that the ES products destabilized LPS-induced cox-2 mRNA in RAW 264.7 macrophages. These results show that ES products from the plerocercoids of Spirometra erinaceieuropaei suppress LPS-induced cox-2 mRNA expression in murine RAW 264.7 macrophages, and may attenuate inflammation around the plerocercoids of S. erinaceieuropaei

A Molecular Variant of the Angiotensinogen Gene and Hypertension in a Case-Control Study in Japanese

In order to examine the distribution of M235T (the substitution of threonine for 0methionine at position 235 codon) polymorphism genotypes of the angiotensinogen (AGT) gene and the relationship between M235T polymorphism of the AGT gene and hypertension, a descriptive study and a case-control study were performed among Japanese workers. The subjects were 2042 workers at an occupational site in Shimane Prefecture in Japan. The database was set up for the workers' regular health examination in 1998. The M235T polymorphism of the AGT gene for each worker was defined by the mutant allele specific amplification (MASA) method. The rates of M235M (MM), M235T (MT) and T235T (TT) genotypes were 3.9%, 30.7% and 65.5%, respectively. The odds ratios of MT and TT against MM for hypertension by univariate analysis were 0.77 [95% confidence interval (CI) 0.27-2.18] and 0.77 (95% CI 0.28-2.14), respectively. The odds ratios of MT and TT against MM for hypertension, adjusted for body mass index, fasting blood sugar, drinking habits, cigarette smoking and exercise in a logistic regression model, were 0.90 (95% CI 0.29-2.74) and 0.87 (95% CI 0.30-2.58), respectively. The data from this study suggests that there may be no relationship between the M235T polymorphism of the AGT gene and hypertension. Further prospective studies are needed to resolve this issue