Role of the Sympathetic Nervous System in Immunity - New Insights to Neuroimmune Biology - page 98

CD40

NE

IL-4R

β 2 AR

Adenylate
cyclase

Class switch
recombination

cAMP

PKA HePTP/p38 MAPK

3 ′ IgH
enhancer

pCREB

OCA-B

IgE

Oct-2

OCA-B

3 ′ IgH
enhancer

IgG1

Figure 5.6 The  2 AR activates unique signaling intermediates to regulate the level of
IgG 1 or IgE produced by a B cell. Although stimulation of the  2 AR results in an increase
in the production level of either IgG 1 or IgE, a unique signaling pathway is activated to
modulate the level of antibody produced. Norepinephrine stimulation of the  2 AR activates
the classic signaling pathway, which involves activation of the enzyme adenylate cyclase to
elevate the level of intracellular cAMP and subsequently activate the level of PKA, which
is involved in modulating the level of both IgG 1 and IgE. However, the pathways appear to
diverge at this point. To modulate the level of IgG 1 , PKA phosphorylates the transcription
factor CREB, which translocates to the nucleus and increases expression of the transcriptional
co-activator protein OCA-B, which binds to the transcription factor Oct-2. The OCA-B/Oct-2
complex then binds to the 3IgH enhancer to increase the rate of IgG 1 mRNA transcription.
To modulate the level of IgE, PKA phosphorylates and inactivates hematopoietic protein
tyrosine phosphatase (HePTP), which frees bound p38 MAPK. Inactivation of HePTP allows
the released free p38 MAPK to become activated, resulting in a higher level of activated
p38 MAPK to increase gene expression of several intracellular and surface molecules that
are proposed to play a role in regulating the rate of IgE mRNA transcription, which is also
regulated by the 3IgH enhancer.