Showing papers by "Shizuo Akira published in 1992"

Interleukin-6 and its receptor: a paradigm for cytokines

Abstract: Many cytokines and cytokine receptors involved in the regulation of hematopoiesis, immune responses, and inflammation have been identified and characterized at the molecular level. Several characteristic features of cytokines, such as pleiotropy and redundancy, are now more clearly understood on the basis of their molecular structures. Accumulating evidence has demonstrated an intimate link between cytokines and various diseases such as allergy, autoimmune diseases, and cancer. The pathogenesis of these diseases and therapies to treat them will be discussed based on insights derived from cytokine research.

IL-6 and NF-IL6 in acute-phase response and viral infection

Abstract: NF-IL6 was originally identified as a DNA-binding protein responsible for IL-1-stimulated IL-6 induction. Direct cloning of NF-IL6 revealed its homology with C/EBP. C/EBP is expressed in liver and adipose tissues and is supposed to regulate several hepatocyte- and adipocyte-specific genes. In contrast, NF-IL6 is suppressed in normal tissues, but is rapidly and drastically induced by LPS or inflammatory cytokines such as IL-1, TNF, and IL-6. NF-IL6 can also bind to the regulatory region of various genes including IL-8, G-CSF, IL-1 and immunoglobulin genes. Furthermore, NF-IL6 is shown to be identical to IL-6DBP, a DNA-binding protein responsible for IL-6-mediated induction in acute-phase proteins, demonstrating that NF-IL6 is responsible for the genes regulated by IL-6. These results indicate that NF-IL6 may be a pleiotropic mediator of many inducible genes involved in acute, immune, and inflammatory responses, like NFkB. In this regard, it is noteworthy that both an NF-IL6 binding site and an NFkB binding site are present in the inducible genes such as IL-6, IL-8, and several acute-phase genes. On the other hand, accumulating evidence has revealed that overproduction of IL-6 may be responsible for the pathogenesis and/or several symptoms of a variety of diseases, including autoimmune diseases, malignancies, and viral diseases. At present, the molecular mechanisms of abnormal expression of the IL-6 gene are not known. Recently it has become evident that interplays between viral proteins and cellular proteins play an important role in viral oncogenesis and infection. The fact that NF-IL6 binds to the enhancer core sequences of various viruses strongly suggests a possible relationship of virus infection and IL-6 expression. In fact some evidence (Mahe et al. 1991, Spergel et al. 1992) indicates that NF-IL6 may interact with viral gene enhancers or viral products, although there are no definite data about the involvement of NF-IL6 in viral pathogenesis. Future studies will be required to clarify whether or not the interplay between NF-IL6 and viral infection is responsible for deregulation of the IL-6 gene.

A member of the C/EBP family, NF-IL6 beta, forms a heterodimer and transcriptionally synergizes with NF-IL6.

Abstract: Using a DNA probe from the DNA-binding portion of the NF-IL6 gene and an antibody against the DNA-binding domain of NF-IL6, we isolated a gene homologous to NF-IL6 in the DNA-binding and leucine zipper domains. This intronless gene, termed NF-IL6 beta encodes a 269-amino acid protein with a potential leucine zipper structure, and the gene product can bind to the CCAAT homology as well as the viral enhancer core sequence, as in the cases of NF-IL6 and C/EBP. This gene is expressed at an undetectable or a minor level in normal tissues but is induced by lipopolysaccharide or inflammatory cytokines, as in the case of NF-IL6. NF-IL6 beta easily forms a heterodimer with NF-IL6 in vitro and the heterodimeric complex binds to the same DNA sequence as the respective homodimers. When examined by transient luciferase assays, NF-IL6 beta is consistently a stronger transactivator than NF-IL6. Furthermore, NF-IL6 beta shows a synergistic transcriptional effect with NF-IL6. These data suggest that NF-IL6 beta is an important transcriptional activator in addition to NF-IL6 in regulation of the genes involved in the immune and inflammatory responses.

NF-IL6, a member of the C/EBP family, regulates E1A-responsive promoters in the absence of E1A.

Abstract: A cDNA encoding NF-IL6, an interleukin-6 (IL-6)-regulated human nuclear factor of the C/EBP family, is demonstrated to complement the transactivation function of E1A. The endogenous NF-IL6 level varies according to cell type and correlates positively with an IL-6-regulated cellular E1A-substituting activity that was described recently (J.M. Spergel and S. Chen-Kiang, Proc. Natl. Acad. Sci. USA 88:6472-6476, 1991). When expressed by transfection in cells which contain low levels of NF-IL6 and are incapable of complementing the function of E1A proteins, NF-IL6 also transactivates the E1A-responsive E2ae and E1B promoters, to the same magnitude as E1A. Activation by NF-IL6 is concentration dependent and sequence specific: mutational studies of the E2ae promoter suggest that the promoter-proximal NF-IL6 recognition site functions as a dominant negative regulatory site whereas the promoter-distal NF-IL6 recognition site is positively regulated at low NF-IL6 concentrations and negatively regulated when the NF-IL6 level is high. Consistent with these functions, NF-IL6 alone is sufficient to complement an E1A deletion mutant dl312 in viral infection, when expressed at appropriate concentrations. These results identify NF-IL6 as a sequence-specific cellular nuclear factor which regulates E1A-responsive genes in the absence of E1A.

Regulation of expression of the interleukin 6 gene: structure and function of the transcription factor NF-IL6.

Abstract: The interleukin 6 (IL-6) promoter is rapidly and transiently activated by other cytokines, including IL-1 and tumour necrosis factor (TNF), as well as by phorbol esters and cyclic AMP agonists. Studies using promoter mutants suggested that an IL-1-responsive element mapped within the -180 to -123 region of the IL-6 promoter. A nuclear factor (NF-IL6) that recognized a unique sequence containing an inverted repeat, ACATTGCACAATCT, was identified within the region. Direct cloning of the human NF-IL6 revealed its similarity to C/EBP, a liver- and adipose tissue-specific transcription factor. C/EBP and NF-IL6 recognize the same nucleotide sequence, but exhibit distinct patterns of expression. NF-IL6 is expressed at a low level in normal tissues, but is rapidly and drastically induced by bacterial lipopolysaccharide (LPS) or inflammatory cytokines such as IL-1, TNF and IL-6. Recently, NF-IL6 has been shown to be identical to IL-6DBP, the DNA-binding protein which is responsible for IL-6-mediated induction of several acute-phase proteins. Evidence that NF-IL6 DNA-binding activity is increased after IL-6 stimulation without increased NF-IL6 protein synthesis demonstrates the importance of post-translational modification. There are some results indicating that phosphorylation is involved in transcriptional and binding activities of NF-IL6. Taken together, these findings indicate that NF-IL6 may be an important transcription factor on the signal transduction pathways of IL-1 and IL-6.