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IL-10 has been referred to as 'macrophage deactivator' because it suppresses macrophage activity by blocking cytokine production and accessory functions. The purpose of this study was to compare the effects of IL-10 on genes that are induced by the well characterized macrophage activators, lipopolysaccharide (LPS) and interferons (IFNs). Using Northern blot analysis to measure the effects of IL-10 on the expression of a large panel of LPS and IFNinducible genes, the data suggest that in murine macrophages IL-10 is not a general suppressor of gene induction but, rather, exerts differential effects on gene expression. Induction of certain genes by LPS was indeed blocked to a great extent (70-80%), while expression of others were less inhibited, not modulated at all, or augmented by IL-10. IFN-α and IFN-γ induce a subset of the genes that are also induced by LPS and, within this subset, IL-10 was found to interfere to a lesser extent with IFN- than LPS-induced gene expression. The participation of NF-KB in the induction of IL-10 inhibitable genes and shared common elements in IFN and IL-10 signaling pathways are discussed as potential explanations for these observations. [ABSTRACT FROM PUBLISHER]

IL-1 and its naturally occurring receptor antagonist, IL-1ra, are primarily synthesized by cells of the monocyte-macrophage lineage. The balance of the relative amounts of these secreted cytokines has major importance in the pathophysiology of various inflammatory disorders, especially bacterial sepsis and some autoimmune diseases. While both the agonist and the antagonist genes belong to the same family, IL-1β and IL-1ra are differentially regulated. In the present study, we examined the effects of macrophage activating factors, bacterial lipopolysaccharide (LPS), IFNα, and IFNγ, on the regulation of IL-1ra and IL-1β mRNA levels in thioglycollate-elicited mouse peritoneal macrophages. LPS-treatment of cultured macrophages resulted in a 3 to 4-fold increase in IL-1ra mRNA which peaked between 6-12 h, then started to decline but remained well above background levels at 24 h. In comparison to IL-1ra, the LPS-induced increase in IL-1β mRNA was larger, peaked earlier (at 2-4 h), and sharply decreased thereafter. In vivo analysis of mRNA from LPS-injected mice showed a similar temporal pattern of IL-1β and IL-1ra gene expression in bone marrow, spleen, and liver. In contrast to the effects of LPS, treatment with IFNα and IFNγ alone failed to affect the expression of either IL-1ra or IL-1β mRNA in vitro. However, in combination with LPS, IFNα and IFNγ had differential effects on the induction of these cytokines: IFNγ, but not IFNα, augmented the expression of LPS-induced IL-1ra. Conversely, both IFNα and IFNγ suppressed the induction of IL-1β mRNA by LPS. Thus, while IFNα only affects LPS-induced IL-1β gene expression, IFNγ exerts opposing effects on the LPS-induction of the agonist and antagonist, illustrating the complex role of interferons during the inflammatory process. [ABSTRACT FROM PUBLISHER]

Interferon-gamma (IFN-gamma) was shown previously to increase Fc gamma receptor (Fc gamma R)-mediated binding and phagocytosis of immunoglobulin G-opsonized erythrocytes in mouse peritoneal exudate macrophages. Glucocorticoids potentiated this effect. We have extended these observations to an investigation of the effects of IFN-gamma and glucocorticoids on steady-state mRNA levels of the three Fc gamma R genes expressed on murine macrophages: Fc gamma RI, Fc gamma RII, and Fc gamma RIII alpha. Fc gamma RI mRNA was present at a barely detectable level in unstimulated cells but was induced 5- to 10-fold by IFN-gamma. Fc gamma RIII alpha mRNA was expressed constitutively and was induced significantly but very modestly (1.5-fold) by IFN-gamma. Fc gamma RII mRNA also exhibited high constitutive expression, but it was not altered by IFN-gamma treatment. Dexamethasone (DEX) significantly increased the expression of IFN-gamma-induced Fc gamma RI mRNA but had no effect on the expression of Fc gamma RII or Fc gamma RIII alpha transcripts in untreated or IFN-gamma-treated cells. The effect of DEX on Fc gamma RI mRNA was seen after about 10 h of simultaneous treatment with IFN-gamma, was dose-dependent, and was glucocorticoid specific. DEX did not modulate the rate of decay of the Fc gamma RI mRNA, suggesting that the up-regulatory effect of DEX may occur, in part, at the level of transcription. In the same culture system, the steady-state level of IFN-gamma-induced Ia mRNA was concurrently inhibited by DEX. The up-regulation of the IFN-gamma-induced high-affinity Fc gamma RI mRNA, the failure to modulate the expression of the two low-affinity Fc gamma R mRNA species, and the down-regulation of IFN-gamma-induced Ia mRNA by DEX in the same cell population illustrate the diverse, gene-specific influence of glucocorticoids on the expression of IFN-gamma-inducible genes.

Steady-state levels of mRNAs that encode specific Fc gamma R and Ia antigen genes have been measured in macrophages treated with interferons (IFNs) to examine the induction of these markers at the molecular level. Our previous studies suggested requirement for protein kinase C (PKC) in the IFN induction of these macrophage surface markers, although a difference in PKC dependence was found between IFN-alpha/beta- and IFN-gamma-induced Fc gamma R expression. The protein kinase antagonist H7, used previously to distinguish between the surface induction of Fc gamma R by IFN-alpha/beta and IFN-gamma, also distinguishes between the IFN-alpha and IFN-gamma in the induction of Fc gamma RI mRNA and Fc gamma RI surface expression. Protein kinase inhibitors blocked the IFN-gamma induction of Ia mRNA in a manner similar to that reported previously for cell surface Ia expression. It is concluded that Fc gamma RI is induced by both IFN-alpha and IFN-gamma through distinct biochemical pathways, whereas IFN-gamma utilizes distinct pathways to induce the two macrophage activation markers, Ia antigen and Fc gamma RI.

Serial cranial ultrasound studies, 133xenon inhalation cerebral blood flow determinations, and risk factor analyses were performed in 31 preterm neonates. Contrast echocardiographic studies were additionally performed in 16 of these 31 infants. Sixty-one percent were found to have germinal matrix or intraventricular hemorrhage. Seventy-four percent of all hemorrhages were detected by the thirtieth postnatal hour. The patients were divided into three groups: early GMH/IVH by the sixth postnatal hour (eight infants) interval GMH/IVH from 6 hours through 5 days (10), and no GMH/IVH (12). Cerebral blood flow values at 6 postnatal hours were significantly lower for the early GMH/IVH group than for the no GMH/IVH group (P less than 0.01). Progression of GMH/IVH was observed only in those infants with early hemorrhage, and these infants had a significantly higher incidence of neonatal mortality. Ventriculomegaly as determined by ultrasound studies was noted equally in infants with and without GMH/IVH (50%) and was not found to correlate with low cerebral blood flow. The patients with early hemorrhage were distinguishable by their need for more vigorous resuscitation at the time of birth and significantly higher ventilator settings during the first 36 postnatal hours, during which time they also had higher values of PCO2. An equal incidence of patent ductus arteriosus was found across all of the groups. We propose that early GMH/IVH may be related to perinatal events and that the significant decrease in cerebral blood flow found in infants with early GMH/IVH is secondary to the presence of the hemorrhage itself. Progression of early GMH/IVH and new interval GMH/IVH may be related to later neonatal events known to alter cerebral blood flow.