Proteomic analysis of the anti‐inflammatory action of minocycline

Abstract

Minocycline possesses anti-inflammatory properties independently of its antibiotic activity although the underlying molecular mechanisms are unclear. Lipopolysaccharide (LPS)-induced cytokines and pro-inflammatory protein expression are reduced by minocycline in cultured macrophages. Here, we tested a range of clinically important tetracycline compounds (oxytetracycline, doxycycline, minocycline and tigecycline) and showed that they all inhibited LPS-induced nitric oxide production. We made the novel finding that tigecycline inhibited LPS-induced nitric oxide production to a greater extent than the other tetracycline compounds tested. To identify potential targets for minocycline, we assessed alterations in the macrophage proteome induced by LPS in the presence or absence of a minocycline pretreatment using 2-DE and nanoLC-MS. We found a number of proteins, mainly involved in cellular metabolism (ATP synthase b-subunit and aldose reductase) or stress response (heat shock proteins), which were altered in expression in response to LPS, some of which were restored, at least in part, by minocycline. This is the first study to document proteomic changes induced by minocycline. The observation that minocycline inhibits some, but not all, of the LPS-induced proteomic changes shows that minocycline specifically affects some signalling pathways and does not completely inhibit macrophage activation.

Immunomodulatory tetracyclines shape the intestinal inflammatory response inducing mucosal healing and resolution

“…In contrast, no significant inhibitory effect was observed for TTC or RFX at the viable concentrations assayed ( Figure 1A). Then, the immunomodulatory tetracyclines were evaluated in BMDM, to characterize the dual anti-/pro-inflammatory activity described in this cell type (Kloppenburg et al, 1996;Dunston et al, 2011;Bonjoch et al, 2015). LPS activation of BMDM induced the expression of Nos2 and the release of IL-1β, IL-6 and TNFα.…”

“…However, the relevance of these activities to the overall anti-inflammatory effect has not been specifically assessed. Of note, although their actions within the immune system are generally anti-inflammatory, a certain degree of controversy has been observed as regards their effects in monocytes and macrophages (Mφ): while immunomodulatory tetracyclines inhibit the inflammatory activity of microglia and peritoneal Mφs, increased activation and cytokine production has been observed in monocytes (Kloppenburg et al, 1996), alveolar Mφs (Bonjoch et al, 2015) and RAW264.7 colonic Mφ cell line (Dunston et al, 2011).…”

Impact of Doxycycline as Malaria Prophylaxis on Risk of Influenza-Like Illness among International Travelers

“…Tetracyclines have a regulatory influence on the immune system and inflammatory pathways. 14,15 Doxycycline has been shown to inhibit activation of macrophages which in turn inhibits tumor necrosis factor (TNF)-α, interleukin (IL) 1b, IL-6, and other pro-inflammatory proteins. Tetracyclines also inhibit lipopolysaccharide-induced nitric oxide production.…”

Therapeutic Potential of Adenosine Transport Modulators for Cardiovascular Protection

“…It is a key enzyme directly involved in cellular energy metabolism and the widely conceived theory of ischemia preconditioning and a target for cardioprotection [26,27]. Pharmacologic agents which activate ATP synthase or maintain its integrity in adversary conditions such as demonstrated for the tetracyclines [28] may help to preserve intracellular ATP in ischemia. On the other hand, adenylate kinases are abundant phosphotransferases catalyzing the inter-conversion of adenine nucleotides and thus regulate the adenine nucleotide ratios in different intracellular compartments.…”