INFLUENCE OF INTERLEUKIN-6 ON NEURAL ACTIVITY AND TRANSCRIPTION OF THE GENE ENCODING CORTICOTROPIN-RELEASING FACTOR IN THE RAT-BRAIN - AN EFFECT DEPENDING UPON THE ROUTE OF ADMINISTRATION

Interleukin-6 (IL-6) is a pleiotropic cytokine produced by Various lym phoid and neural cells. In addition to its classic role during immune and inflammatory responses, IL-6 acts on the central nervous system to elicit changes, such as activation of the hypothalamic-pituitary-adre nal (HPA) axis. This study investigated the effects of systemic and ce ntral injection of IL-6 on neural activity and transcription of the co rticotrophin-releasing factor (CRF) gene in the brain of conscious rat s. The animals were killed 1 and 3 h after a single infusion of IL-6 i nto the right jugular vein (0.83 or 3.0 mu g) or the right lateral ven tricle (0.2 mu g) and their brains cut from the olfactory bulb to the end of the medulla in 30-mu m coronal sections. Messenger RNA encoding the protein Fos, a marker of neural activity, and the neuropeptide CR F were localized by in situ hybridization histochemistry using S-35-la belled exonic and intronic riboprobes. The results show that systemic injection of IL-6 induced specific transcription of c-fos gene in most of the sensorial circumventricular organs, including the organum vasc ulosum lamina terminalis, subfornical organ, median eminence, and area postrema, as well as in the central nucleus of the amygdala and bed n ucleus of the stria terminalis. On the other hand, central injection o f IL-6 increased cellular level of c-fos mRNA in the ependymal layer a nd the walls of the ventricles, meninges, nucleus of the solitary trac t, and circumventricular organs. These effects were rapid and transien t, since the signals for c-fos mRNA were detected I h after both treat ments and vanished 3 h afterwards. Moreover, the CRF gene was not acti vated by either systemic or central administration of IL-6 in the para ventricular nucleus of the hypothalamus. Taken together, these results suggest that circumventricular organs hold a privileged position in m ediating the central effects of systemic IL-6 and that centrally injec ted IL-6 can strongly activate cells of the ventricular system and sur rounding structures. Although this differential circuitry may explain distinct origin-dependent functions of IL-6, this cytokine seems insuf ficient, in itself, to induce transcription of the gene encoding neuro endocrine CRF, the neuropeptide responsible for control of the HPA axi s.