Immunologic role of the cholinergic anti-inflammatory pathway and the nicotinic acetylcholine α7 receptor

Cytokines are small protein molecules that facilitate communication between cells of the immune system and other tissues. Their messenger function elicits responses in other cells, ranging from DNA binding and tissue remodeling to coordinating the local cellular response to inflammation. The magnitude of the cytokine response is regulated closely, because an over- or underabundance of cytokine activity can impair organ function and cause shock and tissue injury. Counterregulatory molecular and humoral mechanisms protect the host from cytokine excess, including the pituitary-adrenal-glucocorticoid system, and the anti-inflammatory cytokine system. These humoral systems are protective, but they are relatively slow-acting, concentration-gradient dependent, and not integrated. We recently discovered that the "cholinergic anti-inflammatory pathway," a nervous system-based, rapid, and locally acting mechanism, can inhibit the cytokine response. Signals transmitted via the vagus nerve converge on cytokine-producing cells that express the nicotinic acetylcholine receptor alpha 7 (nAChR alpha 7). The alpha 7 receptor is an essential component of the cholinergic anti-inflammatory pathway, because activation of this receptor prevents cytokine release. Advances in understanding the molecular structure and function of alpha 7 have begun to provide a better understanding of potential mechanisms regarding its assembly, expression, and cytokine-inhibiting functions. It may be possible to exploit this pathway to therapeutic advantage for diseases caused by excessive cytokine activity.