Tetracyclines inhibit activated B cell function

Tetracyclines have recently been shown to exert a number of pleiotropic ant i-inflammatory and immunomodulatory activities, independent of their antibi otic properties. These include the ability to inhibit metalloproteinases (M P), a class of enzymes involved in crucial cellular functions such as the s hedding 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 mug/ml) sign ificantly 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 Bli mp-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 MIR inhibitors, including tetracycline analogs lacking antibiotic activity and the chemically unrela ted hydroxamate KB8301. These novel, direct effects of MP inhibitors on B l ymphocytes suggest an intrinsic role for MP in B cell activation and likely explain some of the observed in vivo immunomodulatory properties of tetrac yclines. Moreover, these findings have significant implications for tetracy cline therapy in Ig-mediated autoimmune or allergic diseases and raise ques tions about the use of doxycycline-inducible transgenic systems for the stu dy of B cell function.