Research

Background

A) NFκB and JNK signaling in the immune system

The IκB Kinase (IKK)-mediated activation of NFκB transcription factors - through either the canonical or the alternative pathway - and the c-Jun N-terminal Kinase (JNK) signaling pathway play important roles in the regulation of gene expression during immune responses (see Figure 1). They control immune cell development and function, cellular proliferation and cell death.

Fig. 1 Cartoons of the NF-κB and JNK signaling pathways.

Stress, inflammatory stimuli and antigen, amongst other stimuli, activate the NF-κB and JNK signaling cascades. The activation of NFκB transcription factors occurs through two main pathways: the canonical and the alternative NF-κB activation pathway. During canonical signaling upstream mediators activate the IκB kinase (IKK) complex, composed of the two catalytic subunits IKK1 and IKK2 and the regulatory protein NF-κBessential Modulator (NEMO), to phosphorylate inhibitory IκB proteins, leading to their ubiquitination and degradation. NF-κBdimers are then free to bind to DNA and activate gene transcription. Alternative NF-κB signaling is mediated by NF-κB Inducing Kinase (NIK) and IKK1, which induce the partial proteolytical degradation of p100 to p52, which together with RelB transactivates their target genes. Activation of the c-Jun N-terminal Kinase (JNK) proteins via upstream mitogen activated protein kinases leads to activation of transcription factors of the AP-1 family. In addition, JNK proteins regulate protein turnover via the E3 ubiquitin ligase Itch and apoptosis by phosphorylating members of the Bcl2 family of anti-apoptotic proteins.

Canonical NFkB signaling occurs after proinflammatory cytokines, microbial products, or antigen receptor-ligation trigger the IKK complex, comprised of the IKK1 and IKK2 catalytic subunits and a regulatory subunit termed NFκB Essential Modulator (NEMO). The alternative pathway relies on IKK1 and NFκB Inducing Kinase (NIK), is independent of NEMO and IKK2, and is initiated in response to inducers such as B cell-Activating Factor belonging to the TNF Family (BAFF).

C-Jun N-terminal Kinases comprise three isoforms (JNK1-3), which are activated in response to a variety of stress signals. JNKs were named after their ability to phosphorylate the AP-1 transcription factor c-Jun, but JNKs also phosphorylate and regulate the activity of a number of other transcription factors, including ATF2, Elk-1, p53 and c-Myc, as well as Bcl-2 family proteins. Active JNK has been identified in B cell lymphomas, suggesting a role for aberrant JNK-activity in lymphomagenesis.

B) NF-κB activation in human disease

Proteins of the NFkB signaling cascade are implicated in a multitude of acquired and hereditary human disease conditions, ranging from skin disorders and inflammatory diseases to tumorigenesis (recently reviewed in (Karin et al., 2002; Orange et al., 2005)). Constitutive activation of canonical NFkB has been described for Hodgkin’s disease, mucosa-associated lymphoid tissue (MALT) lymphoma and activated B cell-type diffuse large B cell lymphoma (ABC-DLBCL). NFκB transcription factors play roles in these processes by regulating the transcription of genes involved in protection against apoptosis, promotion of inflammation and regulation of proliferation. However, activation of NFκB has dramatically diverse effects in different tissues and cell-lineages and it is therefore instrumental to dissect the cell-type-intrinsic functions of NFkB during different physiological and pathophysiological conditions.

NEMO mutations play an important role in hereditary human disease. Mutations or translocations of the X-chromosome-encoded NEMO gene that lead to complete loss of NEMO result in Incontinentia Pigmenti, which is male lethal and manifests itself in female patients mainly as a progressive inflammatory skin disorder (Smahi et al., 2000). The rare and complex syndrome HED-ID, which combines features of hypohydrotic ectodermal dysplasia (HED) with immunodeficiency (ID), affects nearly exclusively male children and has recently also been linked to genetic alteration of the NEMO gene (Doffinger et al., 2001; Jain et al., 2001; Zonana et al., 2000). HED-ID patients develop skin abnormalities and suffer from unusually severe life-threatening and recurrent bacterial infections in early childhood. (reviewed in (Courtois, 2005; Orange et al., 2005)).