Stat4 Regulates Multiple Components of IFN-γ-Inducing Signaling Pathways1
By V. A. Lawless, Shangming Zhang, O. N. Ozes, Heather A. Bruns, I. Oldham, T. Hoey, M. Grusby, M. Kaplan. Journal of Immunology, 2000
133 citations recorded by the source corpus.
Stat4 is activated in response to IL-12. Most functions of IL-12, including the induction of IFN-γ, are compromised in the absence of Stat4. Since the precise role of Stat4 in IFN-γ induction has not been established, experiments were conducted to examine Stat4 activation of IFN-γ and other genes required for cytokine-induced expression of IFN-γ. We first examined IL-12 signaling components. Basal expression of IL-12Rβ1 and IL-12Rβ2 is decreased in Stat4-deficient cells compared with that in control cells. However, IL-12 was still capable of inducing equivalent phosphorylation of Jak2 and Tyk2 in wild-type and Stat4-deficient activated T cells. We have further determined that other cytokine signaling pathways that induce IFN-γ production are defective in the absence of Stat4. IL-18 induces minimal IFN-γ production from Stat4-deficient activated T cells compared with control cells. This is due to defective IL-18 signaling, which results from the lack of IL-12-induced, and Stat4-dependent, expression of the IL-18R. Following IL-12 pretreatment to induce IL-18R, wild-type, but not Stat4-deficient, activated T cells demonstrated IL-18-induced NF-κB DNA-binding activity. In addition, IL-12-pretreated Stat4-deficient activated T cells have minimal IFN-γ production followed by stimulation with IL-18 alone or in combination with IL-12 compared with control cells. Thus, Stat4 activation by IL-12 is required for the function of multiple cytokine pathways that result in induction of IFN-γ.
Subfields: Cancer Research, Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/8e38b4f639f0749883a7718ac12ee657cae3a4ac
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Citations in the corpus
- T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells (2002, background): “In addition, STAT4-independent IFN-γ production by CD4 + T cells has been reported under some condition”
- Distinct requirements for the naturally occurring splice forms Stat4α and Stat4β in IL‐12 responses (2003, background): “As previously observed (Lawless et al., 2000), there is a 1.5- to 2-fold induction of IL-12Rb2 mRNA following IL-12 stimulation, and this induction is similar between Stat4a- and Stat4b-expressing cells (Figure 5A and B).”