Type I interferons and IL-12: convergence and cross-regulation among mediators of cellular immunity

Abstract

Therapeutic use of type I IFN (IFN‐α/β) has become common. Many of the diverse diseases targeted are marked by pathogenetic abnormalities in cell‐mediated immunity (CMI), these cellular immune responses either causing injury to the host, lacking sufficient vigor for virus or tumor clearance, or both. In general, therapeutic efficacy is limited. It is thus notable that the pleiotropic effects of type I IFN on CMI remain poorly understood. We characterized the effects of type I IFN on the production of IL‐12, the central immunoregulatory cytokine of the CD4+ T cell arm of CMI. We show that type I IFN are potent inhibitors of IL‐12 production by human monocytes/macrophages. The underlying mechanism involves transcriptional inhibition of the IL‐12p40 gene, marked by down‐regulation of PU.1 binding activity at the upstream Ets site of the IL‐12p40 promoter. Type I IFN have previously been shown to be able to substitute for IL‐12 in driving IFN‐γ production from T and NK cells. The ability of IFN‐α/β to suppress IL‐12 production while up‐regulating IFN‐γ production suggests a possible mechanistic basis for the difficulties of employing these cytokines in diseases involving abnormalities of CMI.

Critical Role of MHC Class I-Related Chain A and B Expression on IFN-α-Stimulated Dendritic Cells in NK Cell Activation: Impairment in Chronic Hepatitis C Virus Infection

“…In contrast, IFN-␣ stimulation suppresses IL-12 production in DC/NK coculture (Fig. 5A), which is consistent with previous reports (31)(32)(33), and IL-12 is entirely dispensable for activation of NK cells by IFN-␣-stimulated DCs.…”

Activation of Human NK Cells by Staphylococci and Lactobacilli Requires Cell Contact-Dependent Costimulation by Autologous Monocytes

“…This in turn may profoundly influence the nature of the adaptive immune response. Thus, further to their role in innate defenses against infections, NK cells might be relevant for the microenvironmental regulation of T-cell polarization (3,32). Experimental evidence that selected lactobacilli may participate in the establishment of a particular microenvironment leading to a protective immune response was provided.…”

Direct Effects of Type I Interferons on Cells of the Immune System

“…IFNs-I also affect the ability of DC to secrete IL-12p70. Low concentrations of IFNs-I are essential for the optimal production of IL-12p70 (46), whereas higher levels of IFN-I suppress IL-12p40 expression, thus dampening IL-12p70 production (47).…”