Parathyroid hormone-related protein (PTHrP) induction in reactive astrocytes following brain injury: a possible mediator of CNS inflammation

PTHrP, a peptide induced in parenchymal organs during endotoxemia and in th e synovium in rheumatoid arthritis, has recently been shown to be expressed in immature or transformed human astrocytes, but not in normal cells. This finding has led us to postulate that PTHrP might also be induced in reacti ve astrocytes in inflamed brain and, thus, act as a mediator of CNS inflamm ation. To test this hypothesis, PTHrP expression was examined following cor tical stab wound injury in rats, a classical model of reactive gliosis. To determine whether PTHrP was induced in glia by TNF-alpha, a known mediator of inflammation in brain and of PTHrP induction in peripheral tissues, and to determine whether PTHrP, in turn, mediated inflammatory changes in glia, in vitro studies with rat astrocytes and glial-enriched mixed brain cells were also undertaken. Consistent with previous reports of PTHrP expression in normal brain, neurons were the primary site of immunoreactive PTHrP expr ession in the injured cortex 1 day after stab wound injury. Over the subseq uent 3 days, specific immunostaining for PTHrP and for GFAP, a marker of re active astrocytes, appeared in reactive astrocytes at the wound edge and in perivascular astrocytes, reaching a maximum level of expression at the las t time point examined (day 4). TNF-alpha induced PTHrP expression in astroc yte and glial-enriched brain cells in vitro, suggesting that this pro-infla mmatory peptide was a possible mediator of PTHrP expression in CNS inflamma tion. PTHrP(1-34) acted in an additive fashion with TNF-alpha to induced as trocyte expression of IL-6, a cytokine with demonstrated neuroprotective ef fects. Astrocyte proliferation was inhibited by PTHrP(1-34) and PTHrP(1-141 ), acting via a PTH/PTHrP receptor cAMP signaling pathway. These studies su ggest that PTHrP, analogous to its regulatory functions in other non-CNS mo dels of inflammation, may be an important mediator of the inflammatory resp onse in brain. (C) 2001 Elsevier Science BY. All rights reserved.