Intact noradrenaline transporter is needed for the sympathetic fine-tuning of cytokine balance.

Earlier studies demonstrated that cytokine production is under the tonic control of noradrenaline. As the level and/or the duration of noradrenaline action is regulated by the noradrenaline transporter (NET), which is also a target of antidepressant treatment, we studied its role in the regulation of the cytokine response during inflammation. The endotoxin-evoked tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 response was studied in genetically produced noradrenaline transporter-deficient (NET-KO) mice and by treatment with desipramine, a monoamine uptake-blocker antidepressant. NET-KO mice responded to endotoxin with significantly lower TNF-alpha and interleukin-10 production in comparison to their wild-type counterparts. Functional involvement of both alpha- and beta-adrenoceptors could be demonstrated in our model systems, using 7,8-methylenedioxy-14 alpha-hydroxy-alloberbane.HCl (CH-38083) and propranolol; however, the differences between the two phenotypes remained, suggesting a limited role of alpha-adrenoceptors in the observed changes. Acute treatment of both wild-type and NET-KO mice with desipramine significantly decreased the TNF-alpha response and significantly increased interleukin-10 production, indicating the role of an intact noradrenaline transporter in anti-inflammatory responses.

Endotoxin-induced TNF-alpha production changes inversely to its plasma level during pregnancy.

OBJECTIVE: To study plasma TNF-alpha levels during normal pregnancy and the ex vivo endotoxin-induced TNF-alpha production of peripheral blood cells. STUDY DESIGN: In a longitudinal prospective study the ex vivo endotoxin-induced TNF-alpha production of peripheral blood cells and the plasma level of TNF-alpha in 18 women with uncomplicated pregnancies were determined at the 8th, 17th, 27th and 36th weeks of their pregnancy and 48 h and 6 weeks post-delivery. TNF-alpha levels were determined by ELISA technique. Data were analysed by Student's unpaired t-test. RESULTS: From the second trimester LPS-induced TNF-alpha production increased significantly (P<0.05) compared to non-pregnant values. In contrast, spontaneous TNF-alpha levels decreased with gestational age. Lowest values of plasma TNF-alpha levels and highest values of ex vivo endotoxin-induced TNF-alpha levels were detected at the 27th and 36th gestational weeks, respectively. Both parameters returned to non-pregnant levels after 6 weeks of delivery. CONCLUSION: Gestational age influences TNF-alpha production during normal pregnancy. The observed elevation of inducible TNF-alpha production may contribute to the immune defence of the mother against infections.

The inducibility of TNF-alpha production is different in the granulocytic and monocytic differentiated forms of wild type and CGD-mutant PLB-985 cells.

Chronic granulomatous disease is an inherited disorder associated with a defect in phagocytic cell oxidative metabolism resulting in ineffective microbicidal activity. Consequently, patients with chronic granulomatous disease suffer from recurrent infections. Published data show that besides the failure to produce superoxide and its derivatives, other functional problems can also be found in chronic granulomatous disease-mutant cells. Since in innate immune responses other mediators, such as cytokines, also play an important role, we hypothesized that there may be a disturbance in cytokine production by chronic granulomatous disease-mutant cells as well. To prove this hypothesis, the production of tumour necrosis factor-alpha, an important proinflammatory cytokine, was determined by enzyme-linked immunosorbent assay in wild-type and chronic granulomatous disease-mutant myelomonoblastic PLB-985 cells in their immature, granulocytic and monocytic/macrophage differentiated forms. Tumour necrosis factor-alpha production was induced with N-formyl-L-methionyl-L-leucyl-L-phenylalanine (100 nmol/L), lipopolysaccharide (10 micro g/mL), opsonized zymosan (100 micro g/mL) or phorbol 12-myristate 13-acetate (100 nmol/L) for 24 h. We could demonstrate that: (i) there were marked differences in tumour necrosis factor-alpha production only in the differentiated forms of both wild-type and chronic granulomatous disease-mutant cells, while there were no differences in the case of their immature counterparts; (ii) only chronic granulomatous disease-mutant cells retained sensitivity to phorbol 12-myristate 13-acetate both in their granulocytic and monocytic forms, although phorbol 12-myristate 13-acetate responsiveness was a characteristic of both types of immature cells; (iii) the granulocytic form of wild-type cells produced tumour necrosis factor-alpha after opsonized zymosan stimulation, but such a response was not observed in cells originating from the chronic granulomatous disease-mutant cell line; (iv) with the monocytic forms, significantly higher tumour necrosis factor-alpha production could be induced by lipopolysaccharide in the wild-type cells than in the chronic granulomatous disease-mutant cells, although there was no difference in their lipopolysaccharide receptor CD14 expression. In summary, these data show an altered inducibility of tumour necrosis factor-alpha production by chronic granulomatous disease-mutant cells. Our observations suggest a further defect in differentiated chronic granulomatous disease-mutant cells in addition to the known defect in reduced nicotinamide adenine dinucleotide phosphate oxidase, which may contribute to the development of susceptibility to infections in people with chronic granulomatous disease.