Interleukin-6 Attenuates Serotonin 2A Receptor Signaling by Activating the JAK-STAT Pathway

Abstract

The serotonin 2A (5-HT 2A ) receptor and the proinflammatory cytokine, interleukin-6 (IL-6), have both been implicated in psychiatric disorders. Previously, we demonstrated that these molecules both facilitate cognitive flexibility, a prefrontal cortex-mediated executive function impaired in multiple mental illnesses. In this study, we tested the hypothesis that IL-6 influences 5-HT 2A receptor signaling, providing a potential mechanism by which this cytokine may influence behavior. We first demonstrated that 5-HT 2A receptors and IL-6-mediated STAT3 phosphorylation colocalize in cells of the prefrontal cortex, providing the neuroanatomical substrate for a potential interaction. In the neuronally derived A1A1 cell line, which expresses both IL-6 and 5-HT 2A receptors, we found that IL-6 attenuates inositol phosphate (IP) accumulation in response to the 5-HT 2 agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), suggesting that IL-6 can regulate 5-HT 2A receptor function. To identify the signaling pathway(s) that mediate this effect, we measured DOI-mediated IP accumulation in the presence of IL-6 and either the JAK-STAT inhibitor 124 [(9b,10a,16a,23E )-2,16,20,25-tetrahydroxy-9-methyl-19-norlanosta-1,5,23-triene-3,11,22-trione], JSI-124, or the extracellular signal-regulated kinase inhibitor, 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD-98059). The IL-6 effect was blocked by JSI-124 but not PD-98059. Furthermore, silencing RNA knockdown of either JAK or STAT blocked the IL-6 effect, suggesting that IL-6-induced JAK-STAT activation can regulate 5-HT 2A receptor signaling. Finally, to determine if IL-6 specifically regulates the 5-HT 2A receptor system, we measured IP production mediated by another G q -coupled receptor, bradykinin B2. IL-6 had no effect on bradykinin-mediated IP accumulation, suggesting that regulation may occur at the 5-HT 2A receptor. These results may provide clues to the pathologic mechanisms underlying certain psychiatric disorders and may suggest novel therapeutic strategies for their treatment.

Structural characterization and immunomodulatory effects of polysaccharides from Phellinus linteus and Phellinus igniarius on the IL-6/IL-10 cytokine balance of the mouse macrophage cell lines (RAW 264.7)

“…The antiinflammatory cytokine IL-10 inhibits the production of a number of proinflammatory cytokines such as TNF-α and IL-6 and its role has been demonstrated in models of multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), diabetes, inflammatory bowel disease (IBD) and other autoimmune diseases [38]. Interestingly, IL-6 has been found to attenuate serotonin 2A receptor signalling [40] and is considered an interesting target for treatment of depression [41]. Reduced IL-10, a higher IL-6/IL-10 ratio and the absence of a counter-balancing, immunoregulatory increase in IL-10 in responses to elevated IL-6 concentrations contribute to the pro-inflammatory physiological milieu that is known to be associated with major depression [39], a mental health condition in which feelings of sadness, anger, loss and frustration determine daily life for a longer period of time.…”

“…24 Reduced IL-10, a higher IL-6/IL-10 ratio, the absence of a counter-balancing, and immunoregulatory increase in IL-10 in responses to elevated IL-6 concentrations contribute to the pro-inflammatory physiological milieu that is known to be associated with major depression, 39 a mental health condition in which feelings of sadness, anger, loss and frustration determine daily life for a longer period of time. Interestingly, IL-6 has been found to attenuate serotonin 2A receptor signalling 40 and is considered an interesting target for the treatment of depression. 41 We calculated the IL-6/IL-10 ratio as well as the TNF-α/IL-10 ratio for the different treatments from our ELISA and PCR data.…”

Therapeutic Effects of Extinction Learning as a Model of Exposure Therapy in Rats

“…Samples were stored at − 80°C until assay. Western blots were performed as previously described (Donegan et al, 2015). After transfer, membranes were incubated in polyclonal antibodies to pS6-S240/244 (1 : 2000) and β-tubulin or β-actin (1 : 20 000, Cell Signaling, Beverly, MA) to normalize for loading, followed by anti-rabbit secondary antibody (1 : 20 000, Cell Signaling), and detection with Prime ECL (GE Healthcare, Little Chalfont, UK).…”

Interleukin‑22 modulates cisplatin sensitivity of osteosarcoma cells by regulating the STAT3 signaling pathway

“…JAK2 acts as an upstream kinase to recruit STAT3 monomers in the cytosol, allowing inactive STAT3 to form active dimers that are transferred to the nucleus and bind to DNA, leading to the transcription of target genes (22,23). The activation of JAK2/STAT3 has been implicated in the development and progression of various tumors (24)(25)(26)(27).…”