Nuclear Factor‐κB is Involved in the Catecholaminergic Suppression of Immunocompetent Cells

Abstract

A BSTRACT : Catecholamines are known to exert a powerful impact on the immune system by downregulation of proliferation and differentiation, and induction of apoptosis. However, the mechanism for this regulatory route is still unclear. Therefore well established human monocytic cell-lines and nontransformed human monocytes, obtained from peripheral blood, were incubated with an optimal concentration of LPS and varying concentrations of the catecholamine dopamine. The proliferative response to LPS was determined by [ 3 H]thymidine incorporation, and a significant suppressive effect by dopamine was obtained. LPS-induced binding of NF-B to DNA, determined by electrophoretic mobility shift assay, was inhibited by extrinsic dopamine, leading to a decreased proliferation and cytokine expression. In contrast, the intracellular ceramide concentration was not affected by incubation of peripheral blood lymphocytes with dopamine. Our findings suggest that the NF-B-I-B transcription machinery may well be involved in the catecholaminergic regulation of the immune system, while the ceramide-SAPK/JNK cascade appears not to play a significant role in this suppression.

Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin’s lymphoma

“…We have recently reviewed the literature concerning the presence of DA receptors and DAT on immune cells; previous studies concentrated on T lymphocytes (14,15). Notably, the consistent presence of the D2 ''autoreceptor'' sits comfortably with the concept of lymphocytes as an autonomous dopaminergic system whereby tyrosine hydroxylase-dependent DA synthesis provides a means for autocrine regulation, potentially via apoptosis (38)(39)(40)(41).…”

Age-Associated Remodeling of Neural and Nonneural Thymic Catecholaminergic Network Affects Thymopoietic Productivity

“…Namely, it was shown that CAs stored inside the immune cells may cause oxidative stress and apoptosis via a receptor-independent mechanism [119] . In addition, it was demonstrated that CAs were actively transported from the cytoplasm into the immune cell nucleus, where they can interact with nuclear steroid receptors and nuclear factor NF-B and in turn influence transcription processes relevant for apoptosis [117][118][119] . Thus, it seems likely that newly synthesized NA may be involved in T cell development modulation via intracellular nonreceptor-dependent mechanisms.…”

“…In addition, considering that newly synthesized CAs stored inside the immune cells may trigger apoptosis in these cells [117][118][119] , it may be assumed that increased CAs synthesized by thymocytes in old age may have an adverse effect on thymic T cell output. Namely, it was shown that CAs stored inside the immune cells may cause oxidative stress and apoptosis via a receptor-independent mechanism [119] .…”

Catecholamines—Crafty Weapons in the Inflammatory Arsenal of Immune/Inflammatory Cells or Opening Pandora’s Box?

“…Therefore, it seems likely that catecholamines use intracellular oxidative mechanisms to exert autoregulatory functions on immune cells. Even more importantly, a catecholamine-specific transporter has been described on nuclear membranes of lymphocytes, which actively transports catecholamines from the cytoplasm into the cell nucleus where catecholamines interact with nuclear receptors such as steroid receptors (16,68), influence transcription processes via interaction with nuclear factor (NF-)κB, and modulate apoptosis (69) by facilitating the expression of proto-oncogene Bax while attenuating Bcl-2 expression (16,17). It is noteworthy that the mitochondria-associated MAO and the cytosolic COMT fail to enter the nucleus, posing the important but so far unanswered question of how and by what mechanism intranuclear actions of catecholamines are terminated.…”