Different expression levels of interleukin-36 in asthma phenotypes.

Interleukin (IL)-36 family is closely associated with inflammation and consists of IL-36α, IL-36ß, IL-36γ, and IL-36Ra. The role of IL-36 in the context of asthma and asthmatic phenotypes is not well characterized. We examined the sputum IL-36 levels in patients with different asthma phenotypes in order to unravel the mechanism of IL-36 in different asthma phenotypes. Our objective was to investigate the induced sputum IL-36α, IL-36ß, IL-36γ, and IL-36Ra concentrations in patients with mild asthma, and to analyze the relationship of these markers with lung function and other cytokines in patients with different asthma phenotypes. Induced sputum samples were collected from patients with mild controlled asthma (n = 62, 27 males, age 54.77 ± 15.49) and healthy non-asthmatic controls (n = 16, 10 males, age 54.25 ± 14.60). Inflammatory cell counts in sputum were determined. The concentrations of IL-36 and other cytokines in the sputum supernatant were measured by ELISA and Cytometric Bead Array. This is the first study to report the differential expression of different isoforms of IL-36 in different asthma phenotypes. IL-36α and IL-36ß concentrations were significantly higher in the asthma group (P = 0.003 and 0.031), while IL-36Ra concentrations were significantly lower (P < 0.001) compared to healthy non-asthmatic controls. Sputum IL-36α and IL-36ß concentrations in the neutrophilic asthma group were significantly higher than those in paucigranulocytic asthma (n = 24) and eosinophilic asthma groups (n = 23). IL-36α and IL-36ß showed positive correlation with sputum neutrophils and total cell count (R = 0.689, P < 0.01; R = 0.304, P = 0.008; R = 0.689, P < 0.042; R = 0.253, P = 0.026). In conclusion, IL-36α and IL-36ß may contribute to asthma airway inflammation by promoting neutrophil recruitment in airways. Our study provides insights into the inflammatory pathways of neutrophilic asthma and identifies potential therapeutic target.

Increase in cortical pyramidal cell excitability accompanies depression-like behavior in mice: a transcranial magnetic stimulation study.

Clinical evidence suggests that cortical excitability is increased in depressives. We investigated its cellular basis in a mouse model of depression. In a modified version of forced swimming (FS), mice were initially forced to swim for 5 consecutive days and then were treated daily with repetitive transcranial magnetic stimulation (rTMS) or sham treatment for the following 4 weeks without swimming. On day 2 through day 5, the mice manifested depression-like behaviors. The next and last FS was performed 4 weeks later, which revealed a 4 week maintenance of depression-like behavior in the sham mice. In slices from the sham controls, excitability in cingulate cortex pyramidal cells was elevated in terms of membrane potential and frequencies of spikes evoked by current injection. Depolarized resting potential was shown to depend on suppression of large conductance calcium-activated potassium (BK) channels. This BK channel suppression was confirmed by measuring spike width, which depends on BK channels. Chronic rTMS treatment during the 4 week period significantly reduced the depression-like behavior. In slices obtained from the rTMS mice, normal excitability and BK channel activity were recovered. Expression of a scaffold protein Homer1a was reduced by the FS and reversed by rTMS in the cingulate cortex. Similar recovery in the same behavioral, electrophysiological, and biochemical features was observed after chronic imipramine treatment. The present study demonstrated that manifestation and disappearance of depression-like behavior are in parallel with increase and decrease in cortical neuronal excitability in mice and suggested that regulation of BK channels by Homer1a is involved in this parallelism.

Role of the lateral habenula in shaping context-dependent locomotor activity during cognitive tasks.

Lesions of the lateral habenula are accompanied by cognitive and emotional deficits. Here we examine how the two sets of deficit may be correlated. In the forced swimming test, control rats had reduced motility and showed a depression-like behavior, as expected. In contrast, rats with bilateral lesions of the lateral habenula presented (on day 2) an increased motility over that of the controls, which suggested the presence of hyperactivity and antidepression effect. In addition, the spontaneous activity of the lesioned rats was elevated. We then examined the cognitive deficits in these hyperactive rats. In the contextual fear conditioning, the habenula-lesioned rats did not show the expected freezing and remained hyperactive. In the Morris water maze test, the lesioned rats performed poorly while showing a decreased motor activity. In the active avoidance test, there was no difference in the rate of avoidance between operated and control rats; however, once they failed to change compartments upon the cue, the operated rats tended to remain in the same compartment as under shock, thus showing hypoactivity. In summary, in the lesioned animals the hyperactivity that counteracts the depression-like effect is persistent or inadequately modified in the course of cognitive tasks. We suggest that the lateral habenula is required for regulating emotional influences on locomotor activity, so that the animal's behavior is singularly adapted to different cognitive tasks.