Reciprocal regulation of the junctional proteins claudin-1 and connexin43 by interleukin-1 beta in primary human fetal astrocytes

Vertebrate tissues use multiple junctional types to establish and maintain tissue architecture, including gap junctions for cytoplasmic connectivity a nd tight junctions (TJs) for paracellular and/or cell polarity barriers. Th e integral membrane proteins of gap junctions are connexins, whereas TJs ar e a complex between occludin and members of a recently characterized multig ene family, the claudins. In normal brain, astrocytes are coupled by gap ju nctions composed primarily of connexin43 (Cx43), whereas TJs have not been detected in these cells. We now show that treatment of primary human astroc ytes with the cytokine interleukin-1 beta (IL-1 beta) causes rapid inductio n of claudin-1, with an expression pattern reciprocal to loss of Cx43. Trea tment also led to protracted downregulation of occludin but no change in ex pression of zonula occludens proteins ZO-1 and -2. Immunofluorescence stain ing localized claudin-1 to cell membranes in IL-1 beta -treated astrocytes, whereas freeze-fracture replicas showed strand-like arrays of intramembran ous particles in treated cells resembling rudimentary TJ assemblies. We con clude that in human astrocytes, IL-1 beta regulates expression of the claud in multigene family and that gap and tight junction proteins are inversely regulated by this proinflammatory cytokine. We suggest that in pathological conditions of the human CNS, elevated IL-1 beta expression fundamentally a lters astrocyte-to-astrocyte connectivity.