Regulation of LPS-mediated IL-6 and TNF-α release by serotonin in human differentiated THP-1 cells

Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease that causes irreversible limitations in lung airflow, which is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. COPD is also characterized as chronic bronchitis and emphysema. The impact and burden of COPD on the global population are getting severe, and COPD is projected to be the third leading cause of death worldwide in 2030.

Only half of COPD cases were attributed by cigarette smoking, other risk factors includes demographic and genetic factors, and exposures to air pollution, infections also play another important role in the exacerbation of COPD. Inflammatory cells and other mediators such as cytokines and bacterial infection are responsible for the inflammatory processes in the airways. Lipopolysaccharide (LPS), a constituent of the gram-negative bacteria, is an important signaling molecule in the innate immune system.

Serotonin (5-HT) is a neurotransmitter, it acts on the membrane receptors in the central and peripheral nervous system, as well as in non-neuronal tissues. Serotonin is responsible for bronchoconstriction and vasoconstriction in the airway.

This study aimed to investigate the effects of LPS-induced releases of interleukin (IL)-6 and tumor necrotic factor (TNF)- α and the effects of 5-HT pretreatment on the regulation of LPS-induced releases of IL-6 and TNF-α in the differentiated THP-1 cells (i.e. macrophages). Finally, the study also elucidated whether the effects of 5-HT would be mediated via 5-HT2A receptors. These data demonstrated that LPS caused an elevation of IL-6 and TNF-α releases in differentiated THP-1 cells. There was no effect of 5-HT alone on IL-6 and TNF-α releases, but an inhibition of both LPS-induced IL-6 and TNF-α releases after pretreatment with 5-HT was observed. Despite the presence of 5-HT2A receptors demonstrated by immunohistochemistry in differentiated THP-1 cells, there was only a small inhibitory effect of 5-HT on TNF-α release but not on IL-6 release by two different 5-HT2A receptor antagonists, ketanserin and altanserin.

Taken together, the current findings suggest that 5-HT may perform as an anti-inflammatory mediator at high concentration (up to 1 mM) through non-5-HT2A receptor-mediated response to down-regulate the production of IL-6 and TNF-α. Therefore, 5-HT may be used as a potential treatment to combat gram-negative bacterial infection. However, further investigations are needed to determine the role of 5-HT in the regulation of inflammation.