5/17/2023 0 Comments Flowjo license 10.1r5Interleukin-4 (IL-4) is an important anti-inflammatory cytokine produced by T helper 2 lymphocytes, mast cells, eosinophils, basophils, and macrophages. Importantly, our findings suggest that the IL-4–opioid system should be targeted in the peripheral damaged tissue, since this can be devoid of central and systemic side effects. These actions represent a novel mode of IL-4 action, since its releasing properties have not been so far reported. The opioids were secreted by IL-4 in the intracellular Ca 2+-dependent manner and activated local peripheral opioid receptors. Here, we found that IL-4 injected at the injured nerves attenuates pain by releasing opioid peptides from the infiltrating macrophages in mice. The IL-4-mediated effects are considered to mostly result from the inhibition of the production of proinflammatory mediators (e.g., IL-1β, tumor necrosis factor, prostaglandin E2). SIGNIFICANCE STATEMENT Interleukin-4 (IL-4) is an anti-inflammatory cytokine, which can ameliorate pain. Together, we identified a new opioid mechanism underlying the IL-4-induced antinociception that involves PKA-mediated, PI3K-mediated, ryanodine receptor-mediated, and intracellular Ca 2+-mediated release from M1 macrophages of opioid peptides, which activate peripheral opioid receptors in injured tissue. The IL-4-induced release of ENK was diminished by IL-4Rα antibody, intracellular Ca 2+ chelator, and inhibitors of protein kinase A (PKA), phosphoinositide 3-kinase (PI3K), and ryanodine receptors. ![]() Macrophages isolated from damaged nerves by immunomagnetic separation (IMS) and stimulated with IL-4 dose dependently secreted all three opioid peptides measured by immunoassays. Injured nerves were predominately infiltrated by proinflammatory M1 macrophages and IL-4 did not change their numbers or the phenotype, assessed by flow cytometry and qRT-PCR, respectively. A single application of IL-4 at the injured nerves (14 d following CCI) attenuated mechanical hypersensitivity evaluated by von Frey filaments, which was reversed by co-injected antibody to IL-4Rα, antibodies to opioid peptides such as Met-enkephalin (ENK), β-endorphin and dynorphin A 1–17, and selective antagonists of δ-opioid, µ-opioid, and κ-opioid receptors. As a model of pathologic pain, we used a chronic constriction injury (CCI) of the sciatic nerve in male mice. Here, we uncovered that IL-4 induces acute antinociception by IL-4 receptor α (IL-4Rα)-dependent release of opioid peptides from M1 macrophages at injured nerves. ![]() Classically, IL-4 diminishes pain by blocking the production of proinflammatory cytokines. Interleukin-4 (IL-4) is an anti-inflammatory cytokine, which can be protective in inflammatory and neurologic disorders, and can alleviate pain.
0 Comments
Leave a Reply. |