Multistage Regulation of Th1-Type Immune Responses by the Transcription Factor IRF-1

Abstract

Eradication of a given pathogen is dependent on the selective differentiation of T helper (Th) cells into Th1 or Th2 types. We show here that T cells from mice lacking the transcription factor IRF-1 fail to mount Th1 responses and instead exclusively undergo Th2 differentiation in vitro. Compromised Th1 differentiation is found to be associated with defects in multiple cell types, namely impaired production of interleukin-12 by macrophages, hyporesponsiveness of CD4+ T cells to interleukin-12, and defective development of natural killer cells. These results indicate the involvement of IRF-1 in multiple stages of the Th1 limb of the immune response.

Identification of a TLR4‐ and TRIF‐dependent activation program of dendritic cells

“…In addition, we found that functional TRIF is required for the lipid-A-stimulated upregulation of IRF-1 (Fig. 3), which was also reported to be required for Th1 responses [26,27]. Activation of the TRIF signaling pathway of TLR4 may therefore explain, at least in part, previous observations indicating that coinjection of high doses of LPS and antigen promotes the development of Th1 responses [28,29].…”

Diterpenoids from the Soft Coral <i>Sinularia maxima</i> and Their Inhibitory Effects on Lipopolysaccharide-Stimulated Production of Pro-inflammatory Cytokines in Bone Marrow-Derived Dendritic Cells

“…Note that since IL-12 is a key cytokine in Th1-mediated autoimmune responses, downregulation of IL-12 production by the isolated compounds from the soft coral S. maxima may ameliorate autoimmune diseases. 28,29) In contrast, the bioactive IL-12 cytokine is a heterodimeric p70 molecule and both subunits are co-expressed in the same cell to generate the bioactive form. 26) Regulation of IL-12 p40 production has been investigated at the transcriptional level, in which multiple regulatory elements have been implicated including nuclear factor kappa B (NF-κB), Ets-2, and members of the interferon regulatory factor (IRF) 27) and CCAAT enhancer binding protein (C/EBP) families.…”

Identification of IRF-8 and IRF-1 target genes in activated macrophages

“…For example, IRF-8 null mice fail to mount Th1-mediated immune response, since they fail to produce the IL-12 p40 subunit (Wang et al 2000). Similarly, IRF-1 -/-are also devoid of Th1 responses due to deficiency of the same IL-12 subunit (Taki et al 1997; Lohoff et al 1997). Further, clinical studies have assigned important role for IRF-1 in the onset of myelodysplastic syndromes, which are clonal myeloid disorders (Willman et al 1993).…”