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development. The identification of neuromediator receptors on the plasma membrane
of lymphoid cells explains the ability of these cells to recognize changes in their neu-
romediator microenvironment [68-72] . The open synapse concept helps to explain
how an integrated neuroimmune regulatory circuit is regulated by neuromediators.
Regulatory influences may be transmitted by humoral means, through changes
in blood levels of hormones and regulatory peptides, and, to some extent, through
changes in the blood supply of lymphoid organs. Neuromediator balance influences
the metabolic and functional activity of lymphoid cells [73-76] .
It was discovered that immunocytes at different stages of proliferation and dif-
ferentiation have varying sensitivity to neuromediators. Therefore, the whole process
is multivariant by nature. By the end of the 1980s, studies of ligand-receptor interac-
tions in various lymphoid cells provided evidence for the role of specific neurome-
diators in the activities of lymphocyte populations [68,77-79] .
At present, our knowledge of the biochemical mechanisms of signal transmission
and of the effects of neurohumoral factors on the metabolic and functional activi-
ties of immune cells is incomplete. However, we do know that signal transmission
involves the system of cyclic nucleotides, including cyclic adenosine monophosphate
(cAMP) and cyclic guanosine monophosphate (cGMP), membrane-bound ATPases,
changes in calcium fluxes, and the sphingomyelin pathway [80-83] .
Recent studies indicate that mediators derived from arachidonic acid are neces-
sary for lymphocyte activation. Thus, the conversion of arachidonic acid into pros-
taglandins via the cyclooxygenase pathway leads to increased cAMP generation in
lymphoid cells. In contrast, the conversion of arachidonic acid into hydroxy- and
hydroperoxyeicosatetraenoic acid via the lipoxygenase pathway activates cGMP
production.
Neuroimmune interaction is mediated in part by soluble bioregulators, includ-
ing neurotransmitters and neuropeptides, hormones, cytokines, and chemokines.
Interleukin-1 (IL-1) was the first of the interleukins to be found to convey immune-
derived messages toward the CNS. IL-1 is also one of the key regulators of host
defense reactions, either innate or acquired [84-87] .
Virtually, all known mechanisms of signal transduction have been shown to con-
tribute to communication within the neuroimmune regulatory network. For exam-
ple, IL-1 signals cells in both the immune and nervous systems. The biochemical
responses of cells to IL-1 develop within a few minutes. However, neither the exact
sequence of signaling reactions nor their complete cascades are known. The classical
phosphoinositide pathway, including cyclooxygenase- and lipoxygenase-mediated
metabolism of arachidonic acid, has been shown to be implicated in IL-1 signal
transduction [88-90] . G-proteins are activated as a result of IL-1 action, but they are
not directly involved in IL-1 signal transduction [88,91] .
The discovery of the role of ceramides as secondary messengers resulted in the
identification of the new (and currently well recognized) pathway of cytokine signal
transduction initiated by activation of the membrane-bound neutral sphingomyelinase
[92, 93] . This mechanism, which has been named the sphingomyelin pathway, plays
a role in IL-1 signaling, in lymphocytes and fibroblasts [94,95] and in neurons [96] .
IL-1 action on the CNS involves the type I IL-1 receptor and the sphingomyelin
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