The nuclear factor-kappaB (NF-kappaB)/REL family of transcription factors has a central role in coordinating the expression of a wide variety of genes that control immune responses. There has been intense scientific activity in the NF-kappaB field owing to the involvement of these factors in the activation and regulation of key molecules that are associated with diseases ranging from inflammation to cancer. In this review, we focus on our current understanding of NF-kappaB regulation and its role in the immune system and inflammatory diseases. We also discuss the role of NF-kappaB proteins as potential therapeutic targets in clinical applications.

NF-kappaB regulation in the immune system.

Inflammation is a complex set of interactions among soluble factors and cells that can arise in any tissue in response to traumatic, infectious, post-ischaemic, toxic or autoimmune injury. The process normally leads to recovery from infection and to healing, However, if targeted destruction and assisted repair are not properly phased, inflammation can lead to persistent tissue damage by leukocytes, lymphocytes or collagen. Inflammation may be considered in terms of its checkpoints, where binary or higher-order signals drive each commitment to escalate, go signals trigger stop signals, and molecules responsible for mediating the inflammatory response also suppress it, depending on timing and context. The non-inflammatory state does not arise passively from an absence of inflammatory stimuli; rather, maintenance of health requires the positive actions of specific gene products to suppress reactions to potentially inflammatory stimuli that do not warrant a full response.

Points of control in inflammation

The mammalian Rel/NF-κB family of transcription factors, including RelA, c-Rel, RelB, NF-κB1 (p50 and its precursor p105), and NF-κB2 (p52 and its precursor p100), plays a central role in the immune system by regulating several processes ranging from the development and survival of lymphocytes and lymphoid organs to the control of immune responses and malignant transformation. The five members of the NF-κB family are normally kept inactive in the cytoplasm by interaction with inhibitors called IκBs or the unprocessed forms of NF-κB1 and NF-κB2. A wide variety of signals emanating from antigen receptors, pattern-recognition receptors, receptors for the members of TNF and IL-1 cytokine families, and others induce differential activation of NF-κB heterodimers. Although work over the past two decades has shed significant light on the regulation of NF-κB transcription factors and their functions, much progress has been made in the past two years revealing new insights into the regulation and functions of NF-κB...

Regulation and Function of NF-κB Transcription Factors in the Immune System

30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology

MyD88 is a key downstream adapter for most Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). MyD88 deficiency in mice leads to susceptibility to a broad range of pathogens in experimental settings of infection. We describe a distinct situation in a natural setting of human infection. Nine children with autosomal recessive MyD88 deficiency suffered from life-threatening, often recurrent pyogenic bacterial infections, including invasive pneumococcal disease. However, these patients were otherwise healthy, with normal resistance to other microbes. Their clinical status improved with age, but not due to any cellular leakiness in MyD88 deficiency. The MyD88-dependent TLRs and IL-1Rs are therefore essential for protective immunity to a small number of pyogenic bacteria, but redundant for host defense to most natural infections.

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Pyogenic Bacterial Infections in Humans with MyD88 Deficiency

Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males. In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation. The reasons for cell death in females and in utero lethality in males are unknown. The locus for IP has been linked genetically to the factor VIII gene in Xq28 (ref. 3). The gene for NEMO (NF-kappaB essential modulator)/IKKgamma (IkappaB kinase-gamma) has been mapped to a position 200 kilobases proximal to the factor VIII locus. NEMO is required for the activation of the transcription factor NF-kappaB and is therefore central to many immune, inflammatory and apoptotic pathways. Here we show that most cases of IP are due to mutations of this locus and that a new genomic rearrangement accounts for 80% of new mutations. As a consequence, NF-kappaB activation is defective in IP cells.

Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium.

TO THE EDITOR The involvement of retroviruses and more specifically of viruses belonging to the human T-cell lymphotropic virus (HTLV) family in cutaneous T-cell lymphomas’ (CTCL) pathomechanisms remains a fiercely debated issue. Indeed, this hypothesis has remained attractive owing to the presence of a number of similarities between subsets of HTLV-1-associated adult T-cell leukemia and erythrodermic forms of CTCL. Overall, studies conducted in Europe have been generally negative (Bazarbachi et al., 1993, 1997) with the notable exception of a report from Italy, which claimed the isolation of a new retrovirus distantly related to HTLV-1 (then designated HTLV-V) from a continuous cell line derived from a patient with CD4þ Tac CTCL/leukemia as well as in other patients with CTCL (Manzari et al., 1987). This alleged breakthrough has not been confirmed by subsequent studies, including further investigations conducted by the same team. Another, more recent, report identified HTLV-1 tax-like sequences in blood and saliva from Russian CTCL patients, and established that these sequences were indeed expressed up to the protein level (Morozov et al., 2005). In addition, a significant proportion of USA-based investigations seemed to find out precise clues regarding the presence of retroviral agents close to HTLV-1 in skin lesions and/or peripheral blood in CTCL, and some authors have considered it reasonable to conclude that mycosis fungoides/ Sezary syndrome was an HTLV-associated disease (Hall et al., 1991; Pancake et al., 1995; Khan et al., 1996) even though other studies originating from the same geographical area have remained negative, as have been most of European studies (Wood et al., 1997). The discrepancy in the results and concepts developed in these reports is puzzling, and the fact that these different studies have been conducted with heterogeneous tools makes it difficult to apply strict comparisons. Furthermore, virtually all tools used in these studies, of which most of them have been conducted more than 10 years ago, were either poorly specific (serological tests or identification of viral particles, for instance), or were instead specifically targeting HTLV-1 and notably the tax sequence, thereby significantly reducing the chances to uncover even slightly divergent retroviruses. To overcome this difficulty, we used a recently described powerful semi-nested DNA amplification method (Kim et al., 2006), allowing the amplification of a sequence from the HTLV envelope gene located in the envelope receptor-binding domain (Kim et al., 2004). This PCR amplification of the highly variable envelope region, as Abbreviations: CTCL, cutaneous T-cell lymphoma; HTLV, human T-cell lymphotropic virus; PTLV, primate T-cell lymphotropic virus

T. Bardaro

Papers

Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium.

Absence of HTLV-Related Sequences in Skin Lesions and Peripheral Blood of Cutaneous T-Cell Lymphomas