Protection against endotoxic shock and lipopolysaccharide-induced local inflammation by tetracycline: correlation with inhibition of cytokine secretion

Abstract

Septic shock results from excessive stimulation of host immune cells, particularly monocytes and macrophages, by lipopolysaccharide (LPS) released from gram-negative bacteria. Macrophage-derived cytokines, such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1 beta), have been identified as central mediators in the pathogenesis of septic shock and the resultant mortality. Therefore, these cytokines were targets for experimental therapy for septic shock. Because of tetracycline's ability to intervene in cellular mechanisms involved in cytokine secretion, we tested the effect of tetracycline on LPS-induced septic shock and inflammatory lesions in mice. Tetracycline was found to protect mice against LPS-induced lethality and to abolish clinical signs of LPS-induced inflammatory lesions. This protection correlates with tetracycline's ability to reduce LPS-induced TNF-alpha levels in serum. Furthermore, tetracycline was found to inhibit LPS-induced TNF-alpha and IL-1 beta secretion, but not cytokine mRNA accumulation, in human monocytes in vitro. The results presented here suggest that tetracycline is a potent drug for LPS-induced pathology and that its mechanism of action involves blockage of posttranscriptional events of cytokine production.

Proinflammatory cytokine profile in Vibrio vulnificus septicemic patients' sera

“…Injection of LPS into the bloodstream results in pathophysiological changes that are similar to those seen in septic shock in experimental animals [22] as well as in human volunteers [23,24]. Monocyte-derived proin£ammatory cytokines, particularly TNF-K, IL-1L and IL-6, have been well known to play a pivotal role in the pathogenesis of septic shock [18,19,25]. Many researchers have come to realize the usefulness of the proin£ammatory cytokines as prognostic parameters of individual septicemic patients [12,26,27].…”

“…Owing to the doxycycline therapy, a critical number of V. vulni¢cus, stimulating immune cells to produce TNF-K and IL-1L, should have been removed from the host. Recent studies showed that tetracyclines reduced LPS-induced in£ammatory lesions and TNF-K and IL-1L increase in serum [18,19]. These abilities of tetracycline were found to inhibit LPS-induced TNF-K and IL-1L secretion, but not cytokine mRNA accumulation, in human monocytes in vitro.…”

Inhibition of Matrix Metalloproteinase‐Mediated Periodontal Bone Loss in Rats: A Comparison of 6 Chemically Modified Tetracyclines

“…21,24 LPS can induce monocytes, macrophages, and other mesenchymal cells to produce the cytokines IL-1β and TNF-α. [26][27][28] These cytokines can upregulate the MMPs and serine proteinase synthesis in macrophages, fibroblasts, osteoblasts, and osteoclasts. 29 Their effects can be inhibited by tetracyclines.…”

Modulation of matrix metalloproteinase activities in periodontitis as a treatment strategy

“…Matrix metalloproteinases are now known to degrade and inactivate a 1 -antitrypsin, so that tetracyline-inhibition of the matrix metalloproteinases could protect elastasesusceptible substrates (such as elastic fibers, fibronectin, proteoglycans and tissue inhibitors of matrix metalloproteinases) from proteolytic attack as well (35,50,53). Another potential indirect mechanism by which the tetracyclines may inhibit extracellular matrix breakdown could be through inhibition of activation of pro-tumor necrosis factor-a, hereby leading to a decrease in the formation of the powerful cytokine, tumor necrosis factor-a (77,89). Gearing et al (20) have demonstrated that processing of the tumor necrosis factor-a precursor can be mediated by matrix metalloproteinase enzymes.…”