Adrenergic regulation of p38 MAPK phosphorylation by hematopoietic protein tyrosine phosphatase in human B cells (57.4)

Abstract

Abstract Asthma affects ~300 million people and is responsible for $14 billion in annual medical costs. Therapy utilizes agonists to stimulate the beta-2-adrenergic receptor (β2AR) on lung smooth muscle cells. However, β2AR stimulation on a B cell responding to an allergen in vitro or in vivo increases IgE levels without affecting isotype switching. Elucidating how the β2AR agonist increases IgE production is crucial in blocking this effect on the B cell while maintaining bronchodilation. We have shown that β2AR stimulation on B cells during CD40L/IL-4 priming in vitro induces a PKA-dependent phosphorylation of hematopoietic protein tyrosine phosphatase (HePTP). This releases bound p38 MAPK and allows for its phosphorylation. β2AR deficiency or depletion of the endogenous β2AR agonist norepinephrine in vivo decreases levels of IgE made per B cell and lung inflammation after antigen exposure. It is currently unknown if human HePTP functions in this capacity. We sought to determine if HePTP in human B cells contributed to the β2AR-mediated phosphorylation of p38 MAPK. In comparison to anti-CD40/IL-4-primed CL01 B cells, primed B cells exposed to β2AR agonist had increased HePTP phosphorylation and p38 MAPK phosphorylation. This finding suggests that stimulation of the β2AR on human B cells elevates p38 MAPK phosphorylation through a change in HePTP function to elevate IgE. Thus, HePTP may represent a novel target for regulating IgE levels in human B cells during beta-agonist therapy.