NF-kB signaling pathway
The Nuclear factor kappa B (NF-kB) plays a crucial role
in immune and inflammatory responses through the regulation of genes encoding
pro-inflammatory cytokines, adhesion molecules, chemokines, growth factors and inducible
enzymes. Transcription factors of the NF-kB family are
activated in response to signals that lead to cell growth, differentiation, apoptosis and
other events. NF-kB is activated by signals that activate
Nuclear factor NF-kappa-B inhibitor kinase (IKK) resulting
in the phosphorylation of Nuclear factor of kappa light polypeptide gene enhancer in
B-cells inhibitor (I-kB), this targets
I-kB for degradation in the proteasome and frees the
NF-kB dimer, which then translocates to the nucleus and
activates target genes [1].
Tumor necrosis factor (TNF-alpha) binds to one of two
distinct receptors, Tumor necrosis factor receptor superfamily, member 1A and 1B
(TNF-R1 and TNF-R2), and
triggers activation of the canonical NF-kB signaling
pathway. Upon ligand binding TNF-R1 recruits
TNFRSF1A-associated via death domain (TRADD) which then
activates TNF receptor-associated factor 2 (TRAF2), whereas
TNF-R2 directly interacts with
TRAF2. Subsequent (TRAF2)/
Mitogen-activated protein kinase kinase kinase 14
(NIK(MAP3K14))/
IKK/ I-kB signaling cascade
leads to NF-kB activation [2], [3].
The non-canonical pathway of NF-kB activation is utilized
in response to the ligation of only certain TNF receptor
superfamily members, for example Lymphotoxin beta receptor
(LTBR(TNFRSF3)). In the non-canonical pathway,
TRAF stimulates NIK, which
subsequently activates IKK-alpha by phosphorylation.
IKK-alpha promotes the processing of nuclear factor of kappa
light polypeptide gene enhancer in B-cells 2 (NF-kB2 (p100))
from p100 to p52 form. Further processed NF-kB2 is bound to
V-rel reticuloendotheliosis viral oncogene homolog B (RelB).
NF-kB p52/RelB dimer is translocated into the nucleus to
affect gene transcription. The non-canonical pathway is independent on
IKK-beta and IKK-gamma [1], [4].
T cell receptor (TCR) and CD28 molecule
(CD28) can stimulate NF-KB via
Protein kinase C theta (PKC-theta)-dependent pathway [5], [6], [7]. Also CD28
triggers V-akt murine thymoma viral oncogene homolog 1
(AKT)-mediated pathway [6].
Upon binding of Interleukin 1 (IL-1), the Interleukin 1
receptor type I (IL-1RI) associates with Interleukin 1
receptor accessory protein (IL1RAP), forming a functional
signaling receptor complex that recruits myeloid differentiation primary response gene 88
(MyD88). This leads to the translocation into this complex
of Interleukin-1 receptor-associated kinase (IRAK1/2)
together with Toll interacting protein (TOLLIP).
IRAK1 binds TNF receptor-associated factor 6
(TRAF6). After dissociation from the receptor complex,
IRAK1/TRAF6 induces
NIK or Mitogen-activated protein kinase kinase kinase 1
(MEKK1(MAP3K1))-dependent phosphorylation of
IKK [8].
Lipopolysacccharide (LPS) in
complex with Lipopolysaccharide binding protein (LBP) binds
CD14 molecule (CD14) on the cell membrane. It transfers
LPS to lymphocyte antigen 96
(MD-2) and Toll-like receptor 4
(TLR4). TLR4 via binding
MyD88 [8] and/or possibly Receptor-interacting
serine-threonine kinase 2 (RIPK2) induces
NF-kB-activating cascade [9].
References:
- Liang Y, Zhou Y, Shen P
NF-kappaB and its regulation on the immune system.
Cellular & molecular immunology 2004 Oct;1(5):343-50
- Ding WX, Yin XM
Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury.
Journal of cellular and molecular medicine 2004 Oct-Dec;8(4):445-54
- Bradley JR
TNF-mediated inflammatory disease.
The Journal of pathology 2008 Jan;214(2):149-60
- Orange JS, Levy O, Geha RS
Human disease resulting from gene mutations that interfere with appropriate nuclear factor-kappaB activation.
Immunological reviews 2005 Feb;203:21-37
- Coudronniere N, Villalba M, Englund N, Altman A
NF-kappa B activation induced by T cell receptor/CD28 costimulation is mediated by protein kinase C-theta.
Proceedings of the National Academy of Sciences of the United States of America 2000 Mar 28;97(7):3394-9
- Schmitz ML, Bacher S, Dienz O
NF-kappaB activation pathways induced by T cell costimulation.
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003 Dec;17(15):2187-93
- Li Y, Sedwick CE, Hu J, Altman A
Role for protein kinase Ctheta (PKCtheta) in TCR/CD28-mediated signaling through the canonical but not the non-canonical pathway for NF-kappaB activation.
The Journal of biological chemistry 2005 Jan 14;280(2):1217-23
- Verstrepen L, Bekaert T, Chau TL, Tavernier J, Chariot A, Beyaert R
TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme.
Cellular and molecular life sciences : CMLS 2008 Oct;65(19):2964-78
- Kobayashi K, Inohara N, Hernandez LD, Galan JE, Nu?ez G, Janeway CA, Medzhitov R, Flavell RA
RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems.
Nature 2002 Mar 14;416(6877):194-9