Acute-phase cytokines IL-1 beta and TNF-alpha in brain development

The nervous and the immune systems share several molecules that control the ir development and function. We studied the temporal and spatial distributi on of the immunoreactivity of two acute-phase cytokines, TNF-alpha and IL-1 beta, in the developing sheep neocortex and compared it with the well-desc ribed distribution of fetuin, a fetal glycoprotein also known to modulate t he production of cytokines by lipopolysaccharide (LPS)-stimulated monocytes and macrophages. TNF-alpha was present first at embryonic day 30 (E30) (te rm is 150 days in sheep) as a faint band of immunoreactivity between the ve ntricular zone and the primordial plexiform layer (preplate). IL-1 beta was detected at the first appearance of the cortical plate (E35-E40). Both cyt okines were present on both sides of the cortical plate, which contained fe tuin-positive cells, but was free from cytokine staining. By E60, TNF-alpha immunoreactivity was less prominent than that of IL-1 beta and was confine d to the marginal zone and outer developing white matter; IL-1 beta was pre sent in the marginal zone and in two bands of immunoreactive cells, one at the border of the cortical plate/developing layer VI (cells of neuronal mor phology) and the other at the border of layer V and the developing white ma tter (identified as microglia). By E80, TNF-alpha staining had disappeared and IL-1 beta-immunopositive microglia were no longer detectable. By E100-E 140 only a few immunoreactive cells were identified in layers V-VI; these d id not co-localize with fetuin-positive cells. The differences in distribut ion between fetuin and the two cytokines suggest that the opsonizing role o f fetuin, proposed for monocyte production of cytokines, is probably not pr esent in the developing brain. However, early in neocortical development TN F-alpha and IL-1 beta were present in the subplate zone at a time of intens e synaptogenesis.