Anti-inflammatory effect of honokiol is mediated by PI3K/Akt pathway suppression

Abstract

Aim: In this study, we investigated the regulatory effects of honokiol on various inflammatory events mediated by monocytes/macrophages (U937/RAW264.7 cells) and lymphocytes (splenic lymphocytes and CTLL-2 cells) and their putative action mechanism. Methods: In order to investigate the regulatory effects, various cell lines and primary cells (U937, RAW264.7, CTLL-2 cells, and splenic lymphocytes) were employed and various inflammatory events, such as the production of inflammatory mediators, cell adhesion, cell proliferation, and the early signaling cascade, were chosen. Results: Honokiol strongly inhibited various inflammatory responses, such as: (i) the upregulation of nitric oxide (NO), prostaglandin E 2 and TNF-α production and costimulatory molecule CD80 induced by lipopolysaccharide (LPS); (ii) the functional activation of β1-integrin (CD29) assessed by U937 cell-cell and cell-fibronectin adhesions; (iii) the enhancement of lymphocytes and CD8+CTLL-2 cell proliferation stimulated by LPS, phytohemaglutinin A (PHA), and concanavalin A or interleukin (IL)-2; and (iv) the transcriptional upregulation of inducible NO synthase, TNF-α, cyclooxygenase-2, IL-12, and monocyte chemoattractant protein (MCP)-1. These anti-inflammatory effects of honokiol seem to be mediated by interrupting the early activated intracellular signaling molecule phosphoinositide 3-kinase (PI3K)/Akt, but not Src, the extracellular signal-regulated kinase, and p38, according to pharmacological, biochemical, and functional analyses. Conclusion: These results suggest that honokiol may act as a potent anti-inflammatory agent with multipotential activities due to an inhibitory effect on the PI3K/Akt pathway. Key wordsho nok i ol; ma g nolo l; a nti -infla m ma to ry effe cts; m a croph a ges a nd lym phocyt es; phosphoinositide 3-kinase/Akt pathway

Inhibitory effects of honokiol on LPS and PMA-induced cellular responses of macrophages and monocytes

“…3B, right panel) that was similar to its inhibitory effect on TNF-α production. It has been reported that honokiol blocks iNOS expression at the transcriptional level (9,13). Interestingly, honokiol inhibition appears to be lower in the toll like receptor 2 (TLR2)-mediated signaling pathway.…”

“…These results suggest that honokiol is capable of blocking a common pathway involved in the production of proinflammatory cytokines. Indeed, it has been reported that honokiol suppresses TNF-α production by suppressing a series of activation pathways composed of Akt, IKK, IκBα, and NF-κB, which is a signaling event generally seen under inflammatory conditions (9).…”

“…To date, various pharmacological effects of honokiol, such as neuroprotective, anticancer, cardiotonic, and anti-inflammatory activities have been reported (6)(7)(8). It is believed that the molecular mechanisms involved in honokiol pharmacology are managed by modulation of a signaling cascade composed of Ras, Raf, the extracellular signal-regulated kinase (ERK), and NF-κB/IκB kinase (IKK) in response to TNF-α or LPS stimulation and via control of the cellular redox system (9,10). Although various cellular responses to honokiol treatment have been evaluated, the damage and morphological alteration of cells induced by inflammatory stimuli have not yet been evaluated.…”

Biological activity and toxicity of the Chinese herb Magnolia officinalis Rehder & E. Wilson (Houpo) and its constituents

“…An impressive series of studies has shown that all of these major indicators are positively impacted by Magnolia lignans, even if the full anti-inflammatory mechanisms have not yet been elucidated (Choi et al, 2007;Lin et al, 2007;Munroe et al, 2007;Kang et al, 2008;Lee et al, 2011). Upregulating signaling cascades composed of Ras, Raf, and MAPK, downregulating the activation of NF-κB, and blocking NF-κB activation mediated by CD40 and latent membrane protein 1 are speculated to be the action mechanism of Magnolia lignans (Lin et al, 2007;Kim and Cho, 2008;Lee et al, 2011).…”

“…Toll-like receptor 4 (TLR4)), non-receptor type tyrosine kinases (eg. Src and Syk), serine/threonine kinases (protein kinase C (PKC), PKA, PI3K, and AKT), MAPK, and various redox-sensitive transcription factors, such as NF-κB, are regarded as critical components participating in the process (Kim and Cho, 2008;Simmonds and Foxwell, 2008).…”