Receptor-mediated effects of Δ⁹ -tetrahydrocannabinol and cannabidiol on the inflammatory response of alveolar macrophages

Δ⁹ -Tetrahydrocannabinol (Δ⁹ -THC) and cannabidiol (CBD) are cannabinoids found in Cannabis sativa. While research supports cannabinoids reduce inflammation, the consensus surrounding receptor(s)-mediated effects has yet to be established. Here, we investigated the receptor-mediated properties of Δ⁹ -THC and CBD on alveolar macrophages, an important pulmonary immune cell in direct contact with cannabinoids inhaled by cannabis smokers. MH-S cells, a mouse alveolar macrophage cell line, were exposed to Δ⁹ -THC and CBD, with and without lipopolysaccharide (LPS). Outcomes included RNA-sequencing and cytokine analysis. Δ⁹ -THC and CBD alone did not affect the basal transcriptional response of MH-S cells. In response to LPS, Δ⁹ -THC and CBD significantly reduced the expression of numerous proinflammatory cytokines including tumor necrosis factor-alpha, interleukin (IL)-1β and IL-6, an effect that was dependent on CB₂ . The anti-inflammatory effects of CBD but not Δ⁹ -THC were mediated through a reduction in signaling through nuclear factor-kappa B and extracellular signal-regulated protein kinase 1/2. These results suggest that CBD and Δ⁹ -THC have potent immunomodulatory properties in alveolar macrophages, a cell type important in immune homeostasis in the lungs. Further investigation into the effects of cannabinoids on lung immune cells could lead to the identification of therapies that may ameliorate conditions characterized by inflammation.