The NF-kappaB/Rel signaling system is a paradigm for gene activation in response to inflammatory and menacing stimuli. Given the growing body of evidence showing an important involvement of NF-kappaB for the onset of autoimmune diseases and different types of cancer, NF-kappaB is an important drug target for the adjuvant therapy of these diseases. Great efforts have been made for the development of highly specific NF-kappaB inhibitors, some of them being currently tested in phase II clinical trials. Here we discuss recent progress in the identification of druggable components of the NF-kappaB signaling system and the development and potential use of novel NF-kappaB inhibitors.
A battery of proinflammatory agents triggers the activation of NF-kappaB. This inducible transcription factor participates in the expression of an exceptionally large number of target genes, many of them contributing to the regulation of innate and adaptive immunity. Since some target genes also function as NF-kappaB activators, activation of this transcription factor allows the establishment of a signal amplification loop. Dysregulation of the NF-kappaB system and hyperactivated expression of inflammatory mediators are often found in association with some autoimmune diseases, which occur upon mounting of the adaptive immune response against self-antigens. In this review we summarize the relevance of aberrant NF-kappaB signaling for the development and perpetuation of some autoimmune diseases such as rheumatoid arthritis, diabetes mellitus type 1 and Crohn's disease. The assets and drawbacks of systemic or cell-type specific NF-kappaB inhibitors and their potential use in therapy of autoimmune diseases are critically discussed.
Analysis of knockout mice and of T cells deficient for individual signaling proteins allowed the identification of novel members of the costimulation-induced NF-kappaB activation pathway while biochemical approaches started to unveil their functional mechanisms. These results show that NF-kappaB activation depends on an early wave of tyrosine phosphorylation that allows the inducible formation of multiprotein complexes containing several proteins required for NF-kappaB activation: adaptor proteins including Src homology 2 domain-containing leukocyte phosphoprotein 76 (SLP-76) and proteins with enzymatic activity, such as phospholipase C (PLC) gamma and the exchange factor Vav1. While Vav1 contributes to Rac-dependent reorganization of the actin cytoskeleton, activated PLCgamma1 generates the protein kinase C (PKC) activator diacylglycerol. In T cells, the novel PKC isoform PKCtheta is indispensable for NF-kappaB activation and its enzymatic activity depends on recruitment to the immunological synapse. Downstream from PKCtheta, the caspase recruitment domain (CARD) proteins CARD11/CARMA1 and Bcl10 relay T cell receptor-derived signals to the IkappaB kinase (IKK) complex. Many members of the NF-kappaB activation cascade, including the IKKs, are either constitutively or inducibly translocated to the lipid raft fraction, showing a highly organized spatial distribution of these NF-kappaB activating proteins.
Glucocorticoids (GCs) influence a great variety of cellular functions by at least three important modes of action: the activation (or repression) of genes controlled by binding sites for the glucocorticoid receptor (GR), the induction of apoptosis in lymphocytes and the recently discovered cross-talk to other transcription factors such as NF-U UB.
In the chronic state of inflammatory diseases, cellular signaling networks aimed at combating invading pathogens are often constitutively active and transmit their signals even in the absence of inflammatory agents. Thus, many anti-inflammatory drugs interfere with these dys-and hyperactivated cellular signaling networks or transcription factors. As many signaling molecules fulfill important and essential functions in normal cell physiology, their systemic and long-term inhibition may lead to severe side effects including an impaired immune response. To circumvent these pitfalls, two possibilities are proposed and discussed here: (I) Since many inflammatory diseases such as rheumatoid arthritis or inflammatory bowel disease are restricted to certain cell types or tissues, a new generation of anti-inflammatory drugs would target enzymes that are only operational in these affected tissues. (II) As some signaling pathways affect solely a small subset of inflammatory target genes, their inhibition bears the potential of limiting potential side effects.Abbreviations: COX-2 -cyclooxygenase-2; TNFa -tumor necrosis factor a; IL -interleukin; LPSlipopolysaccharide; MAPKs -mitogen-activated protein kinases; ERK -extracellular-signal-regulated kinase; JNK -c-Jun N-terminal kinase; MAPKKs -MAPK kinases; MAPKKKs -MAPK kinase kinases; MMP -matrix metalloproteinase; TAB1 -transforming growth factor-b-activated protein kinase 1 (TAK1)-binding protein 1; NSAIDs -non-steroidal anti-inflammatory drugs; TCR -T cell receptor; C/EBP -CCAAA/enhancer-binding protein; LTb -lymphotoxin b.
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