NF-IL6 and NF-κB in Cytokine Gene Regulation*

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Introduction

The immune system is regulated through a complicated network modulated by a variety of cytokines and their cognate receptors. Transcriptional activation of inflammatory response genes, such as the genes for cytokines, their receptors, cell adhesion molecules, and acute phase proteins, is regulated by a specific assembly of transcription factors on the enhancers and promoters of these genes. Accumulating evidence indicates that a relatively small number of transcription factors play a critical role in achieving the high level of orchestration required for the complex gene expression involved in the immune response. These include the NF-κB, NF-IL6, CREB/ATF, Jun–Fos, STAT, and NF-AT families of transcription factors. On the other hand, dysfunctional regulation of these transcription factors may induce immunologically mediated diseases. In this review, we highlight how protein–protein interactions between transcription factors may modulate the activation of the cytokine genes. Particular attention is directed to two important families of transcription factors, NF-IL6 and NF-κB.

Section snippets

STRUCTURE AND FUNCTION OF NF-IL6

NF-IL6 was originally identified as a nuclear factor binding to a 14-bp palindromic sequence (ACATTGCACAATCT) within an IL-1 responsive element in the human IL-6 gene (Isshiki et al., 1990). Cloning the cDNA encoding human NF-IL6 revealed that it has a high degree of homology with C/EBP in the carboxy-terminal basic and leucine zipper domains, responsible for DNA binding and dimerization, respectively (Akita et al., 1990). NF-IL6 recognizes the same nucleotide sequences as C/EBP. Both proteins

STRUCTURE AND FUNCTION OF NF-ΚB

NF-κB was originally characterized as a κ immunoglobulin enhancer DNA-binding protein. It is, in fact, involved in the regulation of many genes activated during inflammatory, immune, and acute phase responses. Binding sites for NF-κB were identified in the regulatory regions of some cytokine genes (including the TNF, lymphotoxin, IL-6, IL-8, and β-IFN genes), the IL-2 receptor, class I and class II histocompatibility antigen, several acute phase response genes, as well as several viral

Protein–Protein Interaction in Gene Regulation

The combinatorial effects of transcription factors are very important in gene regulation. The cis elements in the promoters and the factors with which they interact do not function independently. Cooperation between transcription factors and higher order complex formation on the promoter appears to be necessary.

IL-1 GENE REGULATION

Transient transfection demonstrated that two regulatory regions control the induction of the IL-1β gene: the upstream induction sequence (UIS) located between positions -3134 and -2729 bp and the promoter-proximal regulatory elements between positions -131 and + 12 (Shirakawa et al., 1993, Auron and Webb, 1994) (Fig. 6). The UIS is extremely responsive to activation by LPS alone or superresponsive to LPS+dibutyryl cAMP. This region contains two independent enhancer regions, -2782 to -2729 and

NF-IL6KO

NF-IL6 KO mice are viable but highly susceptible to facultative intracellular organisms, such as Listeria monocytogenes and Salmonella typhimurium, due to impairment of bacteria killing by activated macrophages (Tanaka et al., 1995). The induction of various cytokines was examined in NF-IL6 KO mice. RNA was prepared from several sources (resident peritoneal macrophages and proteose peptone-elicited peritoneal macrophages with or without stimulation by LPS in vitro). Reverse-transcribed cDNA was

P50 KO MICE

Mice lacking the p50 subunit of NF-κB show no developmental abnormalities but exhibit multifocal defects in immune responses involving B lymphocytes and a nonspecific response to infection. B cells do not proliferate in response to bacterial LPS and antibody production is impaired (Sha et al., 1995, Snapper et al., 1996). Total serum Ig is approximately 4-fold lower than in the knockout mice and IgE was reduced approximately 40-fold, suggesting an important role of p50 in heavy-chain class

Conclusion

The regulated transcription of genes expressed in the immune system depends on the combinatorial activation of several transcription factors including the NF-IL6, NF-κB, Fos–Jun, CREB/ATF, NF-AT, and STAT families. Even in activation of the same gene, the combinatorial assembly of the transcription factors on the promoter seems to vary depending on the tissue or in response to individual extracellular signals. Indeed, gene knockout experiments have demonstrated the involvement of various

ACKNOWLEDGMENTS

Studies on NF-IL6 in the laboratory of the authors presented in this article were supported in part by grants from the Ministry of Education of Japan. We thank T. Tanaka for the figures and a critical reading.

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    This article was accepted for publication on 27 September 1996.

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