IL-4 signaling, gene transcription regulation, and the control of effector T cells.
ABSTRACT The central goal of our laboratory is to understand the regulation of lymphoid cells through molecular mechanisms of signal transduction and transcriptional control. A long-standing focus has been on changes that influence the effector function of mature lymphocytes. Work in the laboratory is oriented toward the identification of new regulatory mechanisms using cell lines and primary cells, and the validation of these in vitro findings in mouse models of immune responses and diseases. In this review, we summarize key insights into the regulation of T helper cell function during the phase of immunity where effector responses arise de novo. Particular interest has been centered on cytokine gene regulation as part of T cell differentiation into the Th1 and Th2 subsets. Information on IL-4 receptor signaling and the role of NF-kappaB transcription factors is reviewed. Our more recent work is designed to understand how regulation at the Th1/2 effector stages is related to the control of memory T cell survival, immune recall responses, and the role of these responses in immune-mediated disease.
- [show abstract] [hide abstract]
ABSTRACT: Interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha) cooperate to induce the expression of many gene products during inflammation. The present report demonstrates that a portion of this cooperativity is mediated by synergism between two distinct transcription factors: signal transducer and activator of transcription 1 (STAT1) and nuclear factor kappaB (NF-kappaB). IFNgamma and TNFalpha synergistically induce expression of mRNAs encoding interferon regulatory factor-1 (IRF-1), intercellular adhesion molecule-1, Mig (monokine induced by gamma-interferon), and RANTES (regulated on activation normal T cell expressed and secreted) in normal but not STAT1-deficient mouse fibroblasts, indicating a requirement for STAT1. Transient transfection assays in fibroblasts using site-directed mutants of a 1.3-kilobase pair sequence of the IRF-1 gene promoter revealed that the synergy was dependent upon two sequence elements; a STAT binding element and a kappaB motif. Artificial constructs containing a single copy of both a STAT binding element and a kappaB motif linked to the herpes virus thymidine kinase promoter were able to mediate synergistic response to IFNgamma and TNFalpha; such response varied with both the relative spacing and the specific sequence of the regions between these two sites. Cooperatively responsive sequence constructs bound both STAT1alpha and NF-kappaB in nuclear extracts prepared from IFNgamma- and/or TNFalpha-stimulated fibroblasts, although binding of individual factors was not cooperative. Thus, the frequently observed synergy between IFNgamma and TNFalpha in promoting inflammatory response depends in part upon cooperation between STAT1alpha and NF-kappaB, which is most likely mediated by their independent interaction with one or more components of the basal transcription complex.Journal of Biological Chemistry 07/1997; 272(23):14899-907. · 4.65 Impact Factor
- Shock. 01/1997; 8(6):409-414.
- [show abstract] [hide abstract]
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.Immunity 07/1997; 6(6):673-9. · 19.80 Impact Factor