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Abstract
Excessive activation and proliferation of inflammatory cell and uncontrolled release of cytokines and chemokines, also known as cytokine storm, is considered to be the main cause of sepsis. Accumulating evidence has indicated that autophagy may play an important role in regulating immune response and controlling excessive inflammation. Recent studies have showed that minocycline has immunomodulatory effects on cytokine and chemokine production. It has also been reported that minocycline can induce autophagy, suggesting that autophagy may be involved in the process of minocycline regulating inflammation and immune response. However, the precise mechanism is unclear. In the present study, we used enzyme-linked immunosorbent assays (ELISA) to measure the production of cytokines following minocycline treatment of lipopolysaccharide- (LPS-) stimulated THP-1 cells. Western blotting analysis was performed to confirm autophagy and the mTOR signal pathway. Cell proliferation was measured by WST-1 cell proliferation assay. We demonstrated that LPS induced autophagy in a tumor necrosis factor- (TNF-) α-mediated manner, and simultaneously, LPS induced the release of TNF-α to trigger inflammation and activated mammalian target of rapamycin (mTOR) to potentiate cell proliferation. Minocycline, which induces autophagy by inhibiting mTOR, suppresses cytokine production and cell proliferation and protects THP-1 cells from LPS toxicity. Further study demonstrated that there might be an intimate crosstalk between the inhibitor kappa B kinase (IKK)/nuclear factor-kappa B (NF-κB) signaling pathway and autophagy flux in modification of inflammatory responses. In addition, rapamycin, the mTOR inhibitor, has cooperative effect with minocycline on suppression of TNF-α release and induction of autophagy by repressing mTOR. Our data brought a novel clue to evaluate minocycline using as a potential therapeutic medicine for sepsis.
Highlights
Inflammation is a complex biological response to various internal and external stresses such as pathogens or irritants, and an immune response of host to defend harmful invader involving various molecular mediators such as cytokines and chemokines [1]
We reported that minocycline inhibited mammalian target of rapamycin (mTOR), induced autophagy, and suppressed cell proliferation in LPS-stimulated THP-1 cells
It was shown that BAY 11-7082 significantly inhibited autophagy induced by either LPS or minocycline (Figures 5(d) and 5(e)). These results demonstrated that the inhibitor kappa B kinase (IKK)/NF-κB signal pathway was associated with LPS- or Mino-induced autophagy
Summary
Inflammation is a complex biological response to various internal and external stresses such as pathogens or irritants, and an immune response of host to defend harmful invader involving various molecular mediators such as cytokines and chemokines [1]. In recent years, accumulating evidence has indicated that overactivation of immune cell and uncontrolled release of cytokines and chemokines, known as cytokine storm, will contribute to the host excessive immune response and tissue damage, subsequently causing systemic inflammatory response syndrome (SIRS) to deteriorate into sepsis, septic shock, and death [2, 3]. Autophagy is a key catabolic process to degrade intracellular large targets, including damaged protein aggregates, invading microorganisms, and disused organelles [4]. It functions as an innate and adaptive immune response for host to defend against harmful stress and maintain cellar
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