Doxycycline Is Anti-Inflammatory and Inhibits Staphylococcal Exotoxin-Induced Cytokines and Chemokines

Abstract

Proinflammatory cytokines mediate the toxic effect of superantigenic staphylococcal exotoxins (SE). Doxycycline inhibited SE-stimulated T-cell proliferation and production of cytokines and chemokines by human peripheral blood mononuclear cells. These results suggest that the antibiotic doxycycline has anti-inflammatory effects and is therapeutically useful for mitigating the pathogenic effects of SE.Staphylococcal toxic shock syndrome toxin 1 (TSST-1) and the structurally related exotoxins are bacterial exotoxins that bind directly to major histocompatibility complex class II molecules on antigen-presenting cells (1,5,8,18,23) and activate T cells expressing specific V␤ elements (7). These toxins are called superantigens because of their ability to polyclonally stimulate large populations of T cells (1,4,7,14). Thus, staphylococcal exotoxins (SE) are potent activators of the immune system and cause a variety of diseases in humans, including food poisoning, toxic shock, and autoimmune diseases (1,2,6,12,14,22). Their interactions with cells of the immune system result in massive production of proinflammatory cytokines and chemokines (1,4,15,17). The cytokines tumor necrosis factor alpha (TNF-␣), interleukin-1 (IL-1), and gamma interferon (IFN-␥) are key mediators in superantigen-induced toxic shock (1, 21). Both TNF-␣ and IL-1 have potent immunostimulating activities and act synergistically with IFN-␥ to enhance immune reactions and promote tissue injury (16). Consequently, these cytokines are pathogenic at high concentrations in vivo and are responsible for fever and toxic shock induced by SE (13,14,18,19).Doxycycline is a broad-spectrum antibiotic widely used for infections caused by both gram-negative and gram-positive microorganisms. It acts as a bacteriostatic agent and is highly effective against many microorganisms, including Staphylococcus aureus, Streptococcus pyogenes, Bacillus anthracis, and Yersinia pestis. Doxycycline belongs to the tetracycline antibiotic family, the members of which have been shown to have other biological actions independent of their antimicrobial effects (10). Doxycycline inhibits phorbol-12-myristate-13-acetate-mediated matrix metalloproteinase 8 (MMP-8) and MMP-9 in human endothelial cells (11). Doxycycline also decreases elastin degradation and reduces MMP activity in a model of aneurismal disease (3). More recently, doxycycline was shown to inhibit the production of IL-1␤ in lipopolysaccharide-treated corneal epithelial cultures to an extent comparable to that achieved by corticosteroids (25). In vivo, doxycycline protected mice from lethal endotoxemia by downregulating cytokine and nitrate secretion in blood (20). This study was undertaken to determine the modulatory effect of doxycycline on staphylococcal superantigen-induced T-cell activation and cytokine production from human peripheral blood mononuclear cells (PBMC).Purified SEB and TSST-1 were obtained from Toxin Technology (Sarasota, Fla.). The endotoxin content of these preparations was Ͻ1 ng of endotoxin/mg of protei...

Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

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Matrix metalloproteinases in tuberculosis

“…Accumulating evidence demonstrates that doxycycline can suppress immunemediated tissue damage in a variety of inflammatory conditions, such as atherosclerosis [80,81], arthritis [82][83][84], neurocysticercosis [85] and Gram-positive infections [86,87]. Therefore, doxycycline represents a potential agent to globally suppress MMP activity in TB and is cheap, safe and readily available in resource-poor settings.…”

Effects of low-dose doxycycline on cytokine secretion in human monocytes stimulated with Aggregatibacter actinomycetemcomitans

“…However, it is unclear to what extent this low-doses of doxycycline is acting directly on MMP activity or if this reduced activity reflects a generalised anti-inflammatory effect (34)(35)(36)(37). Improving our knowledge of host cytokine regulation in response to bacterial challenge is fundamental to understanding the clinical course of the disease and developing novel treatment strategies for periodontitis (38,39).…”