From Wikipedia, the free encyclopedia
Tumor necrosis factor (TNF,
cachexin or cachectin and formally known as tumor necrosis factor-alpha) is a cytokine involved in systemic
inflammation and
is a member of a group of cytokines that stimulate the acute phase reaction.
The primary role of TNF is in the regulation of immune cells. TNF is also able to induce apoptotic cell death, to
induce inflammation, and to inhibit tumorigenesis and viral
replication. Dysregulation of TNF production has been
implicated in a variety of human diseases, as well as cancer.[1]
Recombinant TNF is used as an immunostimulant under the INN
tasonermin.
Discovery
The theory of an anti-tumoral response of the immune system
in vivo was
recognized 100 years ago by the physician William B. Coley. In 1968, Dr. Gale A
Granger from the University of California,
Irvine, reported a cytotoxic factor produced by lymphocytes and named it lymphotoxin
(LT).[2]
Credit for this discovery is shared by Dr. Nancy H. Ruddle from Yale
University, who reported the same activity in a series of
back-to-back articles published in the same month and year.[3]
Subsequently in 1975 Dr. Lloyd J. Old from Memorial Sloan-Kettering Cancer Center, New
York, reported another cytotoxic factor produced by macrophages, and named it tumor necrosis
factor (TNF).[4]
Both factors were described based on their ability to kill mouse fibrosarcoma L-929
cells.
When the cDNAs encoding LT and TNF were cloned in 1984,[5]
they were revealed to be similar. The binding of TNF to its
receptor and its displacement by LT confirmed the functional homology between the two factors.
The sequential and functional homology of TNF and LT led to the
renaming of TNF as TNFα and LT as
TNFβ. In 1985, Bruce A. Beutler
and Anthony
Cerami discovered that a hormone that induces cachexia and previously-named
cachectin was actually TNF.[6]
These investigators then identified TNF as the key mediator of septic shock in
response to infection.[7]
Subsequently, it was recognized that TNF is the prototypic member
of a large cytokine
family, the TNF family.
Gene
The human TNF gene
(TNFA) was cloned in 1985.[8]
It maps to chromosome
6p21.3, spans about 3 kb and contains 4 exons. The last exon codes for more than 80% of
the secreted protein.[9]
The 3' UTR of TNF alpha contains an AU-rich element (ARE).
Structure
TNF is primarily produced as a 212-amino acid-long type II
transmembrane protein arranged in stable homotrimers.[10][11]
From this membrane-integrated form the soluble homotrimeric
cytokine (sTNF) is released via proteolytic cleavage by the
metalloprotease TNF alpha converting enzyme (TACE, also called ADAM17).[12]
The soluble 51 kDa trimeric sTNF tends to dissociate at
concentrations below the nanomolar range, thereby losing its
bioactivity.
The 17-kilodalton (kDa) TNF protomers (185-amino
acid-long) are composed of two antiparallel β-pleated sheets with antiparallel β-strands,
forming a 'jelly roll' β-structure, typical for the TNF family, but
also found in viral capsid proteins.
Cell
signaling
Two receptors, TNF-R1 (TNF receptor type 1;
CD120a; p55/60) and TNF-R2 (TNF receptor type 2;
CD120b; p75/80), bind to TNF. TNF-R1 is expressed in most tissues,
and can be fully activated by both the membrane-bound and soluble
trimeric forms of TNF, whereas TNF-R2 is found only in cells of the
immune system,
and respond to the membrane-bound form of the TNF homotrimer. As
most information regarding TNF signaling is derived from TNF-R1,
the role of TNF-R2 is likely underestimated.
Signaling pathway of TNF-R1. Dashed grey lines represent multiple
steps.
Upon contact with their ligand, TNF receptors also form trimers, their
tips fitting into the grooves formed between TNF monomers. This
binding causes a conformational change to occur in the receptor,
leading to the dissociation of the inhibitory protein SODD from the
intracellular death domain. This dissociation enables the adaptor protein TRADD to bind to the death domain, serving as a
platform for subsequent protein binding. Following TRADD binding,
three pathways can be initiated.[13][14]
- Activation of NF-kB: TRADD recruits TRAF2 and RIP. TRAF2 in turn recruits the multicomponent protein
kinase IKK, enabling the
serine-threonine kinase RIP to
activate it. An inhibitory protein, IκBα, that normally binds to NF-κB and inhibits
its translocation, is phosphorylated by
IKK and subsequently degraded, releasing NF-κB. NF-κB is a
heterodimeric transcription factor that
translocates to the nucleus and mediates the transcription of
a vast array of proteins involved in cell survival and
proliferation, inflammatory
response, and anti-apoptotic factors.
- Induction of death signaling: Like all
death-domain-containing members of the TNFR superfamily, TNF-R1 is
involved in death signaling.[15]
However, TNF-induced cell death plays only a minor role compared to
its overwhelming functions in the inflammatory process. Its
death-inducing capability is weak compared to other family members
(such as Fas), and often masked by
the anti-apoptotic effects of NF-κB. Nevertheless,
TRADD binds FADD, which then
recruits the cysteine protease caspase-8. A high concentration of caspase-8 induces its
autoproteolytic activation and subsequent cleaving of effector caspases,
leading to cell apoptosis.
The myriad and often-conflicting effects mediated by the above
pathways indicate the existence of extensive cross-talk. For
instance, NF-κB enhances the transcription of C-FLIP, Bcl-2, and cIAP1 / cIAP2, inhibitory proteins that interfere
with death signaling. On the other hand, activated caspases cleave
several components of the NF-κB pathway, including RIP, IKK, and
the subunits of NF-κB itself. Other factors, such as cell type,
concurrent stimulation of other cytokines, or the amount
of reactive oxygen species (ROS)
can shift the balance in favor of one pathway or another. Such
complicated signaling ensures that, whenever TNF is released,
various cells with vastly diverse functions and conditions can all
respond appropriately to inflammation.
Physiology
TNF is produced mainly by macrophages, but they
are produced also by a broad variety of other cell types including
lymphoid cells, mast cells, endothelial cells, cardiac myocytes, adipose tissue, fibroblasts, and neuronal tissue. Large amounts of
TNF are released in response to lipopolysaccharide, other bacterial products, and Interleukin-1 (IL-1).
It has a number of actions on various organ systems, generally
together with IL-1 and Interleukin-6
(IL-6):
A local increase in concentration of TNF will cause the cardinal
signs of Inflammation to occur: heat, swelling, redness, and
pain.
Whereas high concentrations of TNF induce shock-like
symptoms, the prolonged exposure to low concentrations of TNF
can result in cachexia, a
wasting syndrome. This can be found, for example, in cancer patients.
Pharmacology
Main article:
TNF inhibition
Tumor necrosis factor promotes the inflammatory response, which,
in turn, causes many of the clinical problems associated with
autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, Crohn's
disease, psoriasis
and refractory asthma. These
disorders are sometimes treated by using a TNF inhibitor. This inhibition can be
achieved with a monoclonal
antibody such as infliximab (Remicade) or adalimumab (Humira), or
with a circulating receptor fusion protein such as etanercept (Enbrel).
See also
Interactions
Tumor necrosis factor-alpha has been shown to interact with TNFRSF1A.[16][17]
References
- ^ Locksley RM, Killeen N, Lenardo MJ (2001).
"The TNF and TNF receptor superfamilies: integrating mammalian
biology". Cell 104 (4): 487–501. doi:10.1016/S0092-8674(01)00237-9. PMID 11239407.
- ^ Kolb WP, Granger GA (1968). "Lymphocyte in
vitro cytotoxicity: characterization of human lymphotoxin".
Proc. Natl. Acad. Sci. U.S.A. 61 (4):
1250–5. doi:10.1073/pnas.61.4.1250. PMID 5249808.
- ^ Ruddle NH, Waksman BH (December 1968). "Cytotoxicity mediated by
soluble antigen and lymphocytes in delayed hypersensitivity. 3.
Analysis of mechanism". J. Exp. Med.
128 (6): 1267–79. doi:10.1084/jem.128.6.1267. PMID 5693925.
- ^ Carswell EA, Old LJ, Kassel RL, Green S,
Fiore N, Williamson B (1975). "An endotoxin-induced serum factor
that causes necrosis of tumors". Proc. Natl. Acad. Sci.
U.S.A. 72 (9): 3666–70. doi:10.1073/pnas.72.9.3666. PMID 1103152.
- ^ Pennica D, Nedwin GE, Hayflick JS, Seeburg
PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV
(1984). "Human tumour necrosis factor: precursor structure,
expression and homology to lymphotoxin". Nature
312 (5996): 724–9. doi:10.1038/312724a0.
PMID 6392892.
- ^ Beutler B, Greenwald D, Hulmes JD, Chang
M, Pan YC, Mathison J, Ulevitch R, Cerami A (1985). "Identity of
tumour necrosis factor and the macrophage-secreted factor
cachectin". Nature 316 (6028): 552–4. doi:10.1038/316552a0.
PMID 2993897.
- ^ Beutler B, Milsark IW, Cerami AC (August
1985). "Passive immunization against cachectin/tumor necrosis
factor protects mice from lethal effect of endotoxin". Science
(journal) 229 (4716): 869–71. doi:10.1126/science.3895437. PMID 3895437.
- ^ Old LJ (1985). "Tumor necrosis factor
(TNF)". Science 230 (4726): 630–2. doi:10.1126/science.2413547. PMID 2413547.
- ^ Nedwin GE, Naylor SL, Sakaguchi AY, Smith
D, Jarrett-Nedwin J, Pennica D, Goeddel DV, Gray PW (1985). "Human lymphotoxin and tumor
necrosis factor genes: structure, homology and chromosomal
localization". Nucleic Acids Res. 13
(17): 6361–73. doi:10.1093/nar/13.17.6361. PMID 2995927. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=321958&blobtype=pdf.
- ^ Kriegler M, Perez C, DeFay K, Albert I, Lu
SD (1988). "A novel form of TNF/cachectin is a cell surface
cytotoxic transmembrane protein: ramifications for the complex
physiology of TNF". Cell 53 (1): 45–53.
doi:10.1016/0092-8674(88)90486-2. PMID 3349526.
- ^ Tang P, Hung M-C, Klostergaard J (1996).
"Human pro-tumor necrosis factor is a homotrimer".
Biochemistry 35 (25): 8216–25. doi:10.1021/bi952182t.
PMID 8679576.
- ^ Black RA, Rauch CT, Kozlosky CJ, Peschon
JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P,
Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R,
Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP (1997). "A
metalloproteinase disintegrin that releases tumour-necrosis
factor-alpha from cells". Nature 385
(6618): 729–33. doi:10.1038/385729a0.
PMID 9034190.
- ^ Wajant H, Pfizenmaier K, Scheurich P
(2003). "Tumor necrosis factor signaling". Cell Death
Differ. 10 (1): 45–65. doi:10.1038/sj.cdd.4401189. PMID 12655295.
- ^ Chen G, Goeddel DV (2002). "TNF-R1
signaling: a beautiful pathway". Science
296 (5573): 1634–5. doi:10.1126/science.1071924. PMID 12040173.
- ^ Gaur U, Aggarwal BB (2003). "Regulation of
proliferation, survival and apoptosis by members of the TNF
superfamily". Biochem. Pharmacol. 66 (8):
1403–8. doi:10.1016/S0006-2952(03)00490-8. PMID 14555214.
- ^ Bouwmeester, Tewis; Bauch Angela, Ruffner
Heinz, Angrand Pierre-Olivier, Bergamini Giovanna, Croughton Karen,
Cruciat Cristina, Eberhard Dirk, Gagneur Julien, Ghidelli Sonja,
Hopf Carsten, Huhse Bettina, Mangano Raffaella, Michon Anne-Marie,
Schirle Markus, Schlegl Judith, Schwab Markus, Stein Martin A,
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External
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PDB Gallery |
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1a8m: TUMOR NECROSIS FACTOR ALPHA, R31D MUTANT
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1tnf: THE STRUCTURE OF TUMOR NECROSIS FACTOR-ALPHA
AT 2.6 ANGSTROMS RESOLUTION. IMPLICATIONS FOR RECEPTOR BINDING
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2az5: Crystal Structure of TNF-alpha with a small
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2tun: CONFORMATIONAL CHANGES IN THE (ALA-84-VAL)
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4tsv: HIGH RESOLUTION CRYSTAL STRUCTURE OF A HUMAN
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5tsw: HIGH RESOLUTION CRYSTAL STRUCTURE OF A HUMAN
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