Tonic neurogenic inhibition of interleukin-6 secretion from murine spleen caused by opioidergic transmission

Abstract

The peripheral nervous system and the immune system were shown to have neurohumoral interactions. This study extends observations that demonstrated neuronal modulation of spontaneous interleukin-6 (IL-6) secretion in the spleen by norepinephrine (NE) and β-endorphin. Spontaneous IL-6 secretion in vivo was markedly reduced by removal of macrophages with the clodronate technique. Furthermore, spontaneous IL-6 secretion was significantly inhibited at physiological concentrations of cortisol (10−7 M). In the presence of 10−7 M cortisol, addition of norepinephrine (NE; 10−5 M) and isoproterenol (10−6 and 10−5 M) significantly increased spontaneous IL-6 secretion (+20%; P = 0.0280, P = 0.0005, and P = 0.0050, respectively). In contrast, addition of β-endorphin significantly inhibited spontaneous IL-6 secretion in the presence of 10−7 M cortisol (−40%; 10−11 M, P = 0.0410; 10−10 M, P = 0.0005). To study the effect of endogenously released transmitters on spontaneous IL-6 secretion, spleen slices were electrically stimulated with 1, 5, 10, 50, and 100 Hz. Spontaneous IL-6 secretion was markedly reduced at a frequency of 10 Hz with 10−7 M cortisol present ( P < 0.0001). This indicates that the combination of nerve firing at 5–10 Hz and physiological cortisol conditions inhibits spontaneous IL-6 secretion. Inhibition of spontaneous IL-6 secretion from spleen macrophages is most probably due to a net inhibitory effect of opioidergic transmission under these conditions.

The loss of sympathetic nerve fibers in the synovial tissue of patients with rheumatoid arthritis is accompanied by increased norepinephrine release from synovial macrophages

“…Due to the large sample size used to calculate the levels of cytokine secretion, differences in the size of the investigated tissue samples are negligible. This is further supported by extensive superfusion experiments with murine spleen slices (41)(42)(43)(44). In patients with RA, prior administration of drugs (prednisolone, MTX, sulfasalazine, azathioprine, NSAID) did not influence the cytokine secretion during superfusion.…”

Neuronally released sympathetic neurotransmitters stimulate splenic interferon‐γ secretion from T cells in early type II collagen–induced arthritis

“…In our previous experiments in healthy NMRI mice, we observed decreased interleukin‐6 (IL‐6) secretion in the spleens (16–18). Similarly, in our present experiments using electrical stimulation of the spleen slices, we observed decreased production of IFNγ, by ∼50%, in the DBA/1 mice with CIA as compared with a continuous increase of IFNγ in control slices (Figure 4B).…”

“…The dimensionless ratio, calculated as a phi value, Φ = 100 × (cytokine 6 hours /cytokine 2 hours ), was used to standardize the cytokine secretion of each slice at 6 hours (Figure 2B) (for cytokine A, Φ A = 100 × [A 6 hours /A 2 hours ], and for cytokine B, Φ B = 100 × [B 6 hours /B 2 hours ]). This standardization technique was found to be superior to standardization methods that use the leukocyte count of the slice, the wet weight, the dry weight, the volume of the slice, or the protein content (16–18).…”

Life satisfaction and inflammatory biomarkers: The 2008 Scottish Health Survey1

“…We cannot exclude the possibility of residual confounding from unmeasured variables. For example, other explanations of the findings might involve the role of unmeasured positive‐emotion related peptides, such as endorphins and oxytocin, which have a possible role in inhibiting inflammatory responses (Straub, Dorner, Riedel, Kubitza, Van Rooijen, Lang, Schölmerich, & Falk, 1998).…”