Modulation of cytokine production by drugs with antiepileptic or mood stabilizer properties in anti-CD3- and anti-Cd40-stimulated blood in vitro.

Increased cytokine production possibly due to oxidative stress has repeatedly been shown to play a pivotal role in the pathophysiology of epilepsy and bipolar disorder. Recent in vitro and animal studies of valproic acid (VPA) report antioxidative and anti-inflammatory properties, and suppression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α. We tested the effect of drugs with antiepileptic or mood stabilizer properties, namely, primidone (PRM), carbamazepine (CBZ), levetiracetam (LEV), lamotrigine (LTG), VPA, oxcarbazepine (OXC), topiramate (TPM), phenobarbital (PB), and lithium on the production of the following cytokines in vitro: interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-17, IL-22, and TNF-α. We performed a whole blood assay with stimulated blood of 14 healthy female subjects. Anti-human CD3 monoclonal antibody OKT3, combined with 5C3 antibody against CD40, was used as stimulant. We found a significant reduction of IL-1 and IL-2 levels with all tested drugs other than lithium in the CD3/5C3-stimulated blood; VPA led to a decrease in IL-1ß, IL-2, IL-4, IL-6, IL-17, and TNF-α production, which substantiates and adds knowledge to current hypotheses on VPA's anti-inflammatory properties.

Impact of antidepressants on cytokine production of depressed patients in vitro.

The interplay between immune and nervous systems plays a pivotal role in the pathophysiology of depression. In depressive episodes, patients show increased production of pro-inflammatory cytokines such as interleukin (IL)-1ß and tumor necrosis factor (TNF)-α. There is limited information on the effect of antidepressant drugs on cytokines, most studies report on a limited sample of cytokines and none have reported effects on IL-22. We systematically investigated the effect of three antidepressant drugs, citalopram, escitalopram and mirtazapine, on secretion of cytokines IL-1ß, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in a whole blood assay in vitro, using murine anti-human CD3 monoclonal antibody OKT3, and 5C3 monoclonal antibody against CD40, to stimulate T and B cells respectively. Citalopram increased production of IL-1ß, IL-6, TNF-α and IL-22. Mirtazapine increased IL-1ß, TNF-α and IL-22. Escitalopram decreased IL-17 levels. The influence of antidepressants on IL-2 and IL-4 levels was not significant for all three drugs. Compared to escitalopram, citalopram led to higher levels of IL-1ß, IL-6, IL-17 and IL-22; and mirtazapine to higher levels of IL-1ß, IL-17, IL-22 and TNF-α. Mirtazapine and citalopram increased IL-22 production. The differing profile of cytokine production may relate to differences in therapeutic effects, risk of relapse and side effects.

Impact of mood stabilizers and antiepileptic drugs on cytokine production in-vitro.

Changes within the immune system have been reported to contribute to the pathophysiology of bipolar disorder and epilepsy. Interestingly, overlapping results regarding the cytokine system have been found for both diseases, namely alterations of interleukins IL-1ß, IL-2, IL-4, IL-6, and tumor necrosis factor-α (TNF-α). However, the effect of mood stabilizers and antiepileptic drugs (AEDs) on these cytokines has not been systematically evaluated, and their effect on IL-17 and IL-22, other immunologically important cytokines, has not been reported. Therefore, we systematically measured levels of IL-1ß, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in stimulated blood of 14 healthy female subjects in a whole blood assay using the toxic shock syndrome toxin TSST-1 as stimulant. Blood was supplemented with the mood stabilizers or antiepileptic drugs primidone (PRM), carbamazepine (CBZ), levetiracetam (LEV), lamotrigine (LTG), valproic acid (VPA), oxcarbazepine (OXC), topiramate (TPM), phenobarbital (PB), lithium, or no drug. IL-1ß production was significantly decreased by PRM, CBZ, LEV, LTG, OXC, PB and lithium. IL-2 significantly decreased by PRM, CBZ, LEV, LTG, VPA, OXC, TPM and PB. IL-22 significantly increased by PRM, CBZ, LEV, OXC, TPM and lithium and decreased by VPA. TNF-α production significantly decreased under all applied drugs. The mechanism of action and side effects of mood stabilizers and AEDs may involve modulation of IL-1ß, IL-2, IL-22 and TNF-α signaling pathways. IL-22 may be a research target for specific therapeutic effects of mood stabilizers and AEDs. These drugs might influence cytokine production by modulating ion channels and γ-aminobutyric acid (GABA) receptors of immune cells.

Seasonal dynamics of biting midges (Diptera: Ceratopogonidae, Culicoides spp.) on dairy farms of Central Germany during the 2007/2008 epidemic of bluetongue.

The unforeseen outbreak of bluetongue in north-western Europe in August 2006 raised the question, which Culicoides spp. were involved in the transmission of bluetongue virus (BTV). Based on the decision 2007/20/EU of December 2006, a large-scale entomological surveillance programme was initiated in the five affected EU member states including Germany. This paper reports on the entomological findings obtained from March/April 2007 to May 2008 at 15 sampling sites in the federal states of Lower Saxony (eastern region), Mecklenburg-Western Pomerania, Brandenburg and Saxony-Anhalt: The number of captured biting midges in one trap varied from none or few Culicoides during winter (December 2007 to April 2008) to up to more than 12,500 individuals during summer and autumn. Catches of the C. obsoletus group were consistently higher than those of the C. pulicaris group. C. imicola, the principal afro-asiatic vector of BTV, was not detected. High numbers of midges were caught inside the cattle sheds. Eleven pools of biting midges were RT-PCR-positive to BTV-8 including pools of non-engorged midges of the C. obsoletus and of the C. pulicaris groups. The first BTV-genome positive pool of midges was detected in August 2007; the remaining genome-positive pools were detected during October and November 2007.

Feeding patterns of biting midges of the Culicoides obsoletus and Culicoides pulicaris groups on selected farms in Brandenburg, Germany.

Host feeding patterns of engorged sibling species of the Culicoides obsoletus and Culicoides pulicaris groups captured during three nights on two selected farms maintaining either cattle, sheep, horses, and pigs (Seedorf, Brandenburg) or cattle, sheep, moufflons, and red and fallow deer (Paulinenaue, Brandenburg) were determined by polymerase chain reaction amplification using conserved primers and sets of species-specific primers derived from vertebrates mitochondrial cytochrome b. Out of a total of 177 blood meals analysed, 115 (65%) tested positive for a blood meal from vertebrates. 63.5% (n = 73) of the cyt b positive specimens could be further assigned down to the species level. Cattle appeared to be the most attractive hosts for Palaearctic biting midges (79.5%, n = 58) even if other large vertebrates were kept in their immediate vicinity. If pigs or horses were additionally maintained on a farm, they were likewise attacked by biting midges but at a distinctly smaller rate than cattle (pigs 13.7%, horses 2.7%). In this study, game animals appear to be less attractive than cattle since only a few engorged midges had taken a blood meal from red deer (4.1%). None of the blood meals analysed tested positive for sheep. Preliminary results reveal that biting midges of the C. pulicaris and C. obsoletus groups can feed on a range of vertebrate hosts but with a distinct preference for cattle even if other livestock are maintained in adjacent areas.