PACAP as an Intrinsic Regulator of Treg Abundance

PACAP as an Intrinsic Regulator of Treg Abundance

A study published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) provides perhaps the first evidence that endogenous pituitary adenylyl cyclase-activating polypeptide (PACAP) modulates the production or expansion of regulatory T cells (Treg) and T helper (Th)17 lymphocytes.

PACAP is a 38-amino-acid neuropeptide identified in 1989 from ovine hypothalamus and belongs to the secretin family. Its closest family member is vasoactive intestinal peptide (VIP). PACAP is widely distributed in the brain and peripheral organs, particularly the endocrine pancreas, gonads, respiratory and urogenital tracts, and it is capable of eliciting a broad spectrum of biological actions.

PACAP is classically viewed as a neurotransmitter, and is co-stored with acetylcholine in the splanchnic nerve terminals innervating the adrenal medulla. In the adrenal medulla, PACAP is released only at high frequencies of stimulation, contributing to the regulation of epinephrine (adrenaline) secretion, and apparently in the stress signaling at the splanchnic–adrenal synapse.

However, the role of endogenously produced PACAP in immune system homeostasis is poorly understood.

In the PNAS study, Yossan-Var Tan and colleagues from the David Geffen School of Medicine, University of California, Los Angeles, CA, USA used PACAP-deficient (KO) mice and the MOG35–55 EAE model to study the potential actions of endogenous PACAP.

The authors found that the PACAP-deficient mice developed an enhanced experimental autoimmune encephalomyelitis (EAE) when compared to control animals. This was associated with enhanced Th1 and Th17 immune responses, diminished Th2 activity in the CNS and lymph nodes, and a reduction of Treg abundance in the lymph nodes.

Based on previous research PACAP is believed to exert anti-inflammatory effects by inhibiting macrophage activity and inducing a Th2 shift. The PNAS study, however is probably the first to demonstrate PACAP’s immunoregulatory effects on Treg and Th17 lymphocytes. Thus, the study identifies PACAP as one of the few known intrinsic regulators of Treg function and production.

Source: Proc Natl Acad Sci USA 2009, 106:2012
Read more: PNAS


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Source: Cover Image: Structure of the ADCYAP1 protein. Based on PyMOL rendering of PDB 2d2p. Author: Emw. Credit: Wikimedia Commons.

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