No abstract

Sepsis is the principal cause of fatality in the intensive care units worldwide. It involves uncontrolled inflammatory response resulting in multi-organ failure and even death. Micheliolide (MCL), a sesquiterpene lactone, was reported to inhibit dextran sodium sulphate (DSS)-induced inflammatory intestinal disease, colitis-associated cancer and rheumatic arthritis. Nevertheless, the role of MCL in microbial infection and sepsis is unclear. We demonstrated that MCL decreased lipopolysaccharide (LPS, the main cell wall component of Gram-negative bacteria)-mediated production of cytokines (IL-6, TNF-α, MCP-1, etc) in Raw264.7 cells, primary macrophages, dendritic cells and human monocytes. MCL plays an anti-inflammatory role by inhibiting LPS-induced activation of NF-κB and PI3K/Akt/p70S6K pathways. It has negligible impact on the activation of mitogen-activated protein kinase (MAPK) pathways. In the acute peritonitis mouse model, MCL reduced the secretion of IL-6, TNF-α, IL-1β, MCP-1, IFN-β and IL-10 in sera, and ameliorated lung and liver damage. MCL down-regulated the high mortality rate caused by lethal LPS challenge. Collectively, our data illustrated that MCL enabled maintenance of immune equilibrium may represent a potentially new anti-inflammatory and immunosuppressive drug candidate in the treatment of sepsis and septic shock.

This study was carried out to evaluate the effects of a Huaier polysaccharide (TP-1) on the tumor growth and immune function in hepatocellular carcinoma (HCC) H22-based mouse in vivo. Results showed that TP-1 was capable of repressing transplanted H22 solid hepatic tumor cell growth in vivo, prolonging the live time of mice bearing ascetic H22 tumors, and repressing the pulmonary metastasis of H22-bearing mice. Moreover, the relative weight of immune organ (spleen and thymus) and lymphocyte proliferation were improved after TP-1 treatment. Furthermore, the treatment with TP-1 could promote immune-stimulating serum cytokines, such as IL-2 and IFN-γ, but inhibit immune-suppressing serum cytokines IL-10 secretion in H22-bearing mice. Besides, the percentage of CD4+ T cells and NK cells was increased, whereas the number of CD8+ T cells decreased in tumor-bearing mice following TP-1 administration. In addition, this compound displayed little toxic effects to major organ of tumor-bearing mice at the therapeutic dose, such as the liver and kidney. This experimental finding suggested that TP-1 exhibited prominent antitumor activities in vivo via enhancement of host immune system function in H22 tumor-bearing mice. This product could be developed individually as a safe and potent biological response modifier for HCC therapy.

In vivo models have demonstrated that interleukin-13 (IL-13) plays an important role in asthma; however, few studies have evaluated the effect of inhibition of IL-13 on established and persistent disease. In the present study, we have investigated the effect of a therapeutic dosing regimen with an anti-IL-13 monoclonal antibody (mAb) in a chronic mouse model of persistent asthma. BALB/c mice were sensitized to allergen [ovalbumin (OVA); on days 1 and 8] and challenged with OVA weekly from day 22. Anti-IL-13 mAb or vehicle dosing was initiated following two OVA challenges when disease was established. At this time, mice exhibited airway hyperresponsiveness (AHR), increased mucus production, inflammation, and initiation of subepithelial fibrosis compared with saline-challenged mice. Mice received four additional OVA challenges. Treatment with anti-IL-13 mAb inhibited AHR and prevented the further development of subepithelial fibrosis and progression of inflammation. Furthermore, mAb treatment reversed the mucus hyperplasia to basal levels. These effects were associated with an inhibition of cytokines, chemokines, and matrix metalloproteinase-9. These data demonstrate that neutralization of IL-13 can inhibit the progression of established disease in the presence of repeated allergen exposures.Asthma is characterized by the presence of reversible bronchoconstriction, increased sensitivity to specific and nonspecific bronchospasmic agents, and excessive mucus production. These clinical features are accompanied by an underlying pathology of inflammation and airway remodeling. The pathological changes are thought to contribute to the clinical symptoms of the disease (Fireman, 2003). Current therapies for asthma provide symptomatic control but do not halt the underlying disease, highlighting the unmet medical need. Patients are continually exposed to allergens or other bronchospasmic agents that may contribute to the maintenance or progression of persistent disease. Evidence to date suggests that interleukin-13 (IL-13) has an important role in asthma; it is associated with human disease, and preclinical models have demonstrated that it induces many of the features associated with human asthma.Elevated levels of IL-13 mRNA and protein (Huang et al., 1995) have been described in human disease pathogenesis, and polymorphisms in the IL-13 gene have been associated with asthma (Wills-Karp, 2000). Multiple studies have demonstrated that administration of recombinant murine (rm) IL-13 to the lungs of mice induces airway mucus hyperplasia, eosinophilia, and airway hyperresponsiveness (AHR) (Grunig et al., 1998;Wills-Karp et al., 1998;Singer et al., 2002;Kibe et al., 2003; Vargaftig and Singer, 2003a,b). These effects of IL-13 are reproduced in transgenic mouse systems where IL-13 overexpression is induced in a constitutive or inducible manner (Zhu et al., 1999Lanone et al., 2002). Chronic transgenic overexpression of IL-13 also induces subepithelial fibrosis and emphysema. Mice deficient in the IL-13 (and IL-4) signalin...