Activation of the sympathetic nervous system and release of catecholamines, such as norepinephrine (NE), regulate inflammation through interactions with the innate immune system. Although crosstalk between these two systems is clear, the role of NE in mediating inflammatory responses is less clear, with evidence of both pro- and anti-inflammatory effects. To further understand these paradoxical effects of NE, we examined the impact of cellular activation and differentiation on inflammatory cytokine production after NE administration to a human monocyte cell line. Using lipopolysaccharide (LPS) to induce cellular activation, we showed that NE inhibits interleukin (IL)-6 protein release from the monocytic form of the cell, when administered before LPS. However, treating the cells with NE after LPS-induced activation led to a decrease in NE's inhibitory effects. NE inhibition of LPS-induced IL-6 was shown to be mediated by the beta 2-adrenergic receptor (B2-AR) as well as cAMP. Interestingly, the decreased sensitivity to NE following monocyte activation by LPS was found to be mediated by a PKA-dependent decrease in B2-AR mRNA. Indeed, blocking PKA reversed B2-AR mRNA downregulation and restored cell sensitivity to NE. Differentiation of cells from the monocyte state to the macrophage state also resulted in decreased NE sensitivity, likely a result of increased mRNA expression of beta arrestin-2 (BARR-2), which can lead to B2-AR desensitization. Finally, LPS-induced activation of cells in the macrophage state completely abolished NE's anti-inflammatory effects, in association with both decreased B2-AR mRNA as well as decreased mRNA for BARR-2, which can inhibit inflammatory responses. To study the impact of NE on inflammation in vivo, we examined stress-induced NE and IL-6 release in patients with major depression versus healthy controls. We found that patients with depression exhibited reduced sensitivity to NE, as depressed patients with high NE responses to stress exhibited the highest stress-induced IL-6 responses. Taken together, these studies indicate that NE primarily functions to inhibit inflammation. However, the extent of NE's anti-inflammatory action is dynamic and depends on the physiological state of the cell. Dysregulation of NE's anti-inflammatory effects may contribute to pathology in diseases involving inflammation, such as depression.