Role of PI3-kinase in anti-helminth immunity involving IgE and gastrointestinal mast cells

点击翻译按钮获取中文摘要

We have previously shown that class IA phosphoinositide 3-kinase (PI3K) is important in the development of gastrointestinal mast cells and anti-helminth immunity against Strongyloides venezuelensis. Since gastrointestinal mast cells as well as IgE are important in anti-henminth immunity, we examined the role of class IA PI3K in gastrointestinal mast cell differentiation and IgE class stitch recombination using mice deficient for the p85α regulatory subunit of class IA PI3K. c-Kit signal was strongly impaired in p85α-deficient mast cells established from the bone marrow with IL-3 as proliferation and JNK activation in response to SCF was severely impaired in p85α-deficient cultured mast cells. Although the expression of a4 (37 integrin that is critical for cellular migration to the intestine was normal in p85α-deficient mast cells, the binding of a4137 to its ligand, MAdCAM was significantly weaker than that of wild type mast cells and migration of p85α-deficient mast cells as examined … More by haptotaxis on MAdCAM-1 coated surface in response to SCF was also impaired. We conclude from these observations that the lack of gastrointestinal mast cells in p85α-deficient mice is due to the deficiency in both migration to and survival in the intestine. Interestingly, helminth infection induced modest mastocytosis in p85α-deficient mice. It is known that IL-3 plays an important role in helminth-induced mastocytosis. PI3K/IL-3 double deficient mice were significantly more sensitive to the infection by S. venezuelensis than each single deficient mouse line as mastocytosis in the intestine and the induction of serum mMCP1 were severely impaired in double deficient mice. These results indicate that production of IL-3 likely supports mastocytosis in 85a-deficient mice. We also examined the role of PI3K in IgE production and found that p85α-deficient mice produced increasing amounts of serum IgE. Purified p85α-deficient B cells produced more IgE than wild type B cells in vitro in response to anti-CD40 mAb and IL-4. PI3K inhibitors wortmannin and IC87114 enhanced IgE production by wild type B cells stimulated with anti-CD40 mAb and IL-4. Under the same condition, antigen receptor cross-linking induced the expression of inhibitor of differentiation-2 (Id2) and suppressed the expression of activation induced cytidine deaminase (AID) and class switch recombination(CSR) in a PI3K-dependent manner. IgE production was also suppressed in a concentrated cell culture condition, which was completely reversed by PI3K inhibition. The selective suppression of IgE production by PI3K was also observed at a protein level after CSR. Our results indicate that PI3K negatively regulates IgE production at both CSR and protein levels. Less