cell biochemistry and function Cell Biochem Funct 2004; 22: 67–79. Published online 4 February 2004 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1027/cbf.1082 REVIEW ARTICLE Signal transduction via the NF-B pathway: a targeted treatment modality for infection, inﬂammation and repair Shakir Ali y and Derek A. Mann* Division of Infection, Inﬂammation and Repair, Southampton University Hospital, Southampton, UK Activation of transcription factors plays a pivotal role in many signal transduction pathways. Of particular interest is NF-B, which is present in the cytoplasm in an inactive form, where it can be activated in response to many different stress condi- tions such as infection, inﬂammation, heat shock etc. It has also been associated with apoptosis and tissue repair. Modulation of signal transduction events that mediate activation of NF-B seems to have a great potential in not only treating many disease conditions, but also in tissue repair. The present review article is an attempt to put together many different conditions where the NF-B activation pathway appears to be crucial in transducing signals under stress conditions, and to explore the possibility of its modulation as a targeted treatment modality. Copyright # 2004 John Wiley & Sons, Ltd. INTRODUCTION NF-B is a dimer of members of the Rel family of DNA-binding proteins, which are characterized by the presence of an N-terminal 300-amino acid con- served sequence, known as ‘rel homology domain’ (RHD). RHD, as revealed by the structural studies, forms a unique butterﬂy-shaped structure composed of  strands arranged in a pattern similar to immuno- globulin domains. This region is responsible for dimer- ization, DNA binding, and interaction with inhibitory cytoplasmic IB proteins, as well as containing a nuclear localization sequence (NLS), 1 which promotes NF-B translocation to the nucleus. In the nucleus, NF- B recognizes the B sites bearing a consensus sequence 5 0 GGG.Pu.N.Py.CC (where, Pu is purine, Py is pyrimidine, and N is any base). NF-B is, in fact, a heterogenous collection of dimers composed of var- ious combinations of members of the Rel family pro- teins, which in eukaryotes, include p50 (NF-B1), p52 (NF-B2), Rel (c-Rel), p65 (RelA), and RelB. 2 Nearly all NF-B proteins have been crystallized and their structures have been determined. NF-B usually refers to a heterodimer of p50:p65, which is the most abundant and also the ﬁrst form of NF-B to be reported. Other heterodimers as well as homodimers also exist to varying degrees in different cell types and exhibit distinct binding afﬁnities for B sites in the enhancer and promoter regions of many genes. Although most NF-B proteins are transcrip- tionally active, some combinations such as p50 homo- dimers and also p52 homodimers are transcriptionally repressive. 3 First described in 1986 4,5 as a nuclear factor neces- sary for immunoglobulin  light chain transcription in B cells, NF-B is now known to exist in virtually all cell types 6 and organelles such as mitochondria. 7 It regulates the transcription of an exceptionally large number of genes including those involved in immune and inﬂammatory responses. 8 In certain situations, it acts as an anti-apoptotic protein, through induction of survival genes. 9 Disorders including arthritis, 10 asthma, 11 inﬂammatory responses 12 and a variety of cancers, 13 virus infections, 14,15 liver ﬁbrosis 16 have been linked to the inappropriate regulation of NF- B. Individual members of the Rel family have been investigated and found to be critical under disease conditions. 17,18 Received 20 February 2003 Revised 8 May 2003 Accepted 14 May 2003 Copyright # 2004 John Wiley & Sons, Ltd. Published online 4 February 2004 * Correspondence to: Dr D. A. Mann, Division of Infection, Inﬂammation and Repair, Southampton University Hospital, Tremona Road, Southampton, SO16 6YD. Fax: 023 8079 6883. E-mail: dam2@soton.ac.uk y SA is presently on sabbatical from Department of Biochemistry, Faculty of Science, Jamia Hamdard (University), New Delhi— 1100 62, India.