Tetracyclines inhibit activated B cell function

Abstract

Tetracyclines have recently been shown to exert a number of pleiotropic anti-inflammatory and immunomodulatory activities, independent of their antibiotic properties. These include the ability to inhibit metalloproteinases (MP), a class of enzymes involved in crucial cellular functions such as the shedding of soluble mediators and their receptors from the cell surface, as well as interaction with, and remodeling of, the extracellular matrix. Here we report that doxycycline at therapeutic concentrations (1--5 microg/ml) significantly suppresses Ig secretion and class switching by in vitro activated murine B cells. Suppression of Ig secretion correlates with a decrease in levels of mRNA for the terminal B cell differentiation-associated genes Blimp-1 and mad-4, as well as to a reduction in expression of the plasma cell markers Syndecan-1 and J chain. Inhibition of class switching occurs at the recombination stage and is also induced by other MP inhibitors, including tetracycline analogs lacking antibiotic activity and the chemically unrelated hydroxamate KB8301. These novel, direct effects of MP inhibitors on B lymphocytes suggest an intrinsic role for MP in B cell activation and likely explain some of the observed in vivo immunomodulatory properties of tetracyclines. Moreover, these findings have significant implications for tetracycline therapy in Ig-mediated autoimmune or allergic diseases and raise questions about the use of doxycycline-inducible transgenic systems for the study of B cell function.

Minocycline treatment results in reduced oral steroid requirements in adult asthma

“…44 In previous work done by Botero and colleagues, doxycycline at therapeutic concentrations suppressed immunoglobulin secretion and class switching by activated murine B cells in vitro with resultant decreased production of IgE and other isotypes. 45 Although total serum IgE levels did not change during the 8 weeks of minocycline treatment in this study, there was a significant decrease in oral steroid require- Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm ments for subjects with elevated total serum IgE.…”

Ability of the hydrophobic FGF and basic TAT peptides to promote cellular uptake of recombinant Cre recombinase: A tool for efficient genetic engineering of mammalian genomes

“…The leakiness of the system represents a critical factor because a Cre recombinase that is undesirably active before induction often leads to unwanted side effects such as mosaic recombination and͞or selection of recombined or nonrecombined cells both in vivo and in vitro (9,17,18). Moreover, the widely used inducers IFN, hydroxy-tamoxifen, and doxycycline are known to display toxic side effects (19,20) and͞or induce also unwanted physiological effects that may interfere with the experimental phenotype of the conditional mutation to be analyzed (21,22). In cultured cells, Cre-mediated recombination is limited by transfection efficiencies and putative toxicity of the protein (13,23,24).…”

Reduction of adhesion formation and promotion of wound healing after laminectomy by pharmacological inhibition of pro-inflammatory cytokines: an experimental study in the rat

“…The data certainly support this initial observation but the information is too limited to allow for any general conclusions. Doxycycline is basically an antibiotic but since it has metal-ion binding properties it may inhibit the action of matrix metalloproteinases that activates certain cytokines by shedding them from the cell membrane in their former inactive form [24,25]. In this sense, doxycycline also acts as a non-specific inhibitor of other pro-inflammatory cytokines such as TNF, IL-1, IL-6 and IFN-gamma [26,27].…”