Modulation of serotonin transporter function by interleukin-4

Serotonin (5-HT) is an important mediator of interactions between the nervo us and immune systems. 5-HT signaling is regulated by the 5-HT transporter (5-HTT), which determines the magnitude and duration of serotonergic respon ses. Due to this important role, regulation of the 5-HTT by cytokines has b een the focus of recent interest. A number of proinflammatory cytokines, in cluding interleukin-1 beta, tumor necrosis factor-or, and interferon-gamma, have been shown to upregulate the 5-HTT. In the present study we investiga ted the influence of interleukin-4, (IL-4), which acts as an anti-inflammat ory cytokine in the central nervous system, on the 5-HTT. As a model system we used immortalized B lymphocytes, which not only express the 5-HTT, but also allow testing the co-modulatory influence of a recently described poly morphism in the 5-HTT gene promoter (5-HTTLPR) that is associated with anxi ety- and depression-related behavioral traits. The results show that IL-4 i nduces a dose dependent reduction of 5-HT uptake. This effect is preferenti ally seen in cell lines homozygous for the long, high-activity allele of th e 5-HTTLPR. In conclusion, a picture of differential modulation of the 5-HT T by proinflammatory and anti-inflammatory cytokines is emerging, which may represent a fine-tuned mechanism to communicate the state of an immune res ponse to the central nervous system. (C) 2001 Elsevier Science Inc. All rig hts reserved.