Tetracyclines downregulate the production of LPS-induced cytokines and chemokines in THP-1 cells via ERK, p38, and nuclear factor-κB signaling pathways

Abstract

Recent reports have shown that antibiotics such as macrolide, aminoglycoside, and tetracyclines have immunomodulatory effects in addition to essential antibiotic effects. These agents may have important effects on the regulation of cytokine and chemokine production. However, the precise mechanism is unknown. This time, we used Multi Plex to measure the production of cytokines and chemokines following tetracycline treatment of lipopolysaccharide (LPS)-induced THP-1 cells. The signaling pathways were investigated with Western blotting analysis. Three tetracyclines significantly suppressed the expression of cytokines and chemokines induced by LPS. Minocycline (50 μg/ml), tigecycline (50 μg/ml), or doxycycline (50 μg/ml) were added after treatment with LPS (10 μg/ml). Tumor necrosis factor-α was downregulated to 16%, 14%, and 8%, respectively, after 60 min compared to treatment with LPS without agents. Interleukin-8 was downregulated to 43%, 32%, and 26% at 60 min. Macrophage inflammatory protein (MIP)-1α was downregulated to 23%, 33%, and 16% at 120 min. MIP-1β was downregulated to 21%, 11%, and 2% at 120 min. Concerning about signaling pathways, the mechanisms of the three tetracyclines might not be the same. Although the three tetracyclines showed some differences in the time course, tetracyclines modulated phosphorylation of the NF-κB pathway, p38 and ERK1/2/MAPK pathways, resulting in inhibition of cytokine and chemokine production. In addition, SB203580 (p38 inhibitor) and U0126 (ERK1/2 inhibitor) significantly suppressed the expression of TNF-α and IL-8 in LPS-stimulated THP-1 cells. And further, the NF-κB inhibitor, BAY11-7082, almost completely suppressed LPS-induced these two cytokines production. Thus, more than one signaling pathway may be involved in tetracyclines downregulation of the expression of LPS-induced cytokines and chemokines in THP-1 cells. And among the three signaling pathways, NF-κB pathway might be the dominant pathway on tetracyclines modification the LPS-induced cytokines production in THP-1 cells. In general, minocycline and doxycycline suppressed the production of cytokines and chemokines in LPS-stimulated THP-1 cell lines via mainly the inhibition of phosphorylation of NF-κB pathways. Tigecycline has the same structure as the other tetracyclines, however, it showed the different properties of cytokine modulation in the experimental time course.

Lipopolysaccharide-induced inflammation in monocytes/macrophages is blocked by liposomal delivery of G_i-protein inhibitor

“…Activation of ERK was not observed, probably because of the prolonged stimulation, ERK being phosphorylated after 30-60 minutes in THP1 monocytes. 31 In accordance with other studies, we show here that G i s are involved in MAPK activation induced by LPS, demonstrated by the reduction in p38 and JNK phosphorylation after treatment of monocytes with GOT. 5 Moreover, Lipo/GOT significantly reduced the phosphorylation of p38 and JNK compared with free GOT.…”

Natural antiviral compound silvestrol modulates human monocyte‐derived macrophages and dendritic cells

“…Similarly, tetracyclines down-regulate the production of LPS-induced chemokines, such as CXCL8, CCL3 and CCL4 in THP-1 cells via NFκB signalling pathways. 46 The antiviral drug acyclovir inhibits the migratory potential of breast cancer cells. 47 These data indicate that silvestrol possibly attenuates inflammation by a reduction of immune cell attraction to the lesion site.…”

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

“…Treatment of prion-infected mice with the tetracycline antibiotics (doxycycline, minocycline and tetracycline) around the onset of the clinical phase has been shown to extend survival times [ 197 ]. Tetracycline antibiotics can suppress cytokine synthesis [ 198 ] and this might have a beneficial effect on CNS prion disease by reducing systemic inflammation. However, these antibiotics have also been shown to block PrP C –PrP Sc conversion and neurotoxicity [ 199 ].…”