The IL-1 family of cytokines currently consists of 11 members which are encoded by
distinct genes and includes IL-1α, IL-1β, and the IL-1 Receptor antagonist (IL-1RA)
(1) . The major role of IL-1 type cytokines is to control pro-inflammatory reactions in
response to tissue injury - either due to pathogen-associated molecular patterns (PAMPs)
or Danger associated molecular patterns (DAMPs) (2). Interleukin-1 (IL-1), which
includes IL-1α and IL-1β, plays a crucial role in many auto inflammatory diseases. IL-
1α and IL-1β are produced predominantly by macrophages and monocytes (3-5), and
to a lesser extent by other cell types such as epithelial cells (6) endothelial cells (7)
and fibroblasts (8). IL-1 alpha, is a membrane anchored protein which signals through
autocrine or juxtracrine mechanisms where as the soluble IL-1 beta acts in a paracrine
or systemic manner (9, 10). Significant progress has been achieved in the study of the
signaling events mediated by IL-1 and the processes they control. Involvement of IL-1α
or IL-1β in host responses to infections caused by intracellular microorganisms such as
Mycobacterium tuberculosis as well as in autoinflammatory diseases makes its signaling
components important candidates for drug targetting for these diseases (11, 12).
The two forms of IL-1 (IL-1α and IL-1β) bind to the same cellular receptor, the Type I IL-
1 receptor (IL-1RI) to induce signaling. Upon receptor engagement, IL-1R1 forms a
heterodimer with IL-1 receptor accessory protein (IL-1RAcP), which functions as a co
receptor (13). IL-1RAcP cannot bind directly to IL-1 but is essential for IL-1-mediated
signaling. Binding of IL-1 to this receptor complex leads to the activation of the
transcription factor NF-kappaB through different signaling mechanisms. Two IL-1
receptor-associated kinases, IRAK-1 and IRAK-2 have been implicated in the activation
of NF-kappaB (14). IRAK 1 and 2 functions as adapter proteins and protein kinases to
transmit downstream signals (15). It recruits TRAF6 to the IL-1 receptor complex via an
interaction with IL-1RAcP. Oligomerization of TRAF6 and subsequent formation of
TAK1 and MEKK3 signaling complexes relays the signal via NF-kappaB-inducing
kinase (NIK) to two I-kappaB kinases (IKK-1 and -2), leading to NF-kappaB activation
(16,17). Activation of other mitogen activated protein kinases, including JNKs and p38
MAPK through various MAP2Ks also play important roles in mediating IL-1 responses
by activating transcription through the AP-1 transcription factor (18-27). The above
mentioned signaling events co-operatively induce the expression of IL-1 target genes
such as CCL2, IL-8 and IL-6 (28). The interactions and intersections between canonical
and non-canonical Interleukin-1 signaling systems are depicted in the pathway map.
Regulation of IL-1 signaling can be brought about by various mechanisms. The IL-1
family member IL-1RA can bind to the IL1-R1 receptor with similar affinity as IL-1
alpha and beta, but is incapable of activating the signaling response. The type II IL-1
receptor can bind to IL-1 alpha and beta but lacks signaling capacity. The naturally
occurring 'shed' domains of the extracellular IL-1 receptor chains (IL-1RI, IL-1RII and IL-
1RAcP) also act as inhibitors of IL-1 signalling (29). In the cell, IL-1R binds to toll-
interacting protein (TOLLIP), which results in the inhibition of IRAK1 and by promoting
efficient degradation of IL-1R by targeting the internalized receptor to endosomes (30-
32). Other mechanisms such as p38MAPK mediated phosphorylation of TAB1 which
results in the inactivation of TAK1, and expression of genes including MAPK
phosphatase 1 (MKP-1) and Inhibitor of kappa B alpha (NFKBIA) that inhibit IL-1
signaling components also serve as negative regulators of IL-1 signaling (33-36).
1. T.T. Pizarro, F.Cominelli (2007) Cloning IL-1 and the birth of a new era in
cytokine biology. J Immunol., 178(9):5411-12.
2. Gaestel M, Kotlyarov A, Kracht M (2009) Targeting innate immunity protein
kinase signalling in inflammation. Nat Rev Drug Discov., 8(6):480-99.
3. Dinarello CA, Ikejima T, Warner SJ, Orencole SF, Lonnemann G, Cannon JG,
Libby P (1987) Interleukin 1 induces interleukin 1. I. Induction of circulating
interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro. J
4. Granowitz EV, Clark BD, Vannier E, Callahan MV, Dinarello CA (1992)
Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: I. IL-1 receptor
antagonist inhibits IL-1-induced cytokine synthesis and blocks the binding of
IL-1 to its type II receptor on human monocytes. Blood., 79(9):2356–63.
5. Netea MG, Nold-Petry CA, Nold MF, Joosten LA, Opitz B, van der Meer JH,
van de Veerdonk FL, Ferwerda G, Heinhuis B, Devesa I, Funk CJ, Mason RJ,
Kullberg BJ, Rubartelli A, van der Meer JW, Dinarello CA (2009) Differential
requirement for the activation of the inflammasome for processing and release
of IL-1beta in monocytes and macrophages. Blood., 113(10), 2324–35.
6. Hoffmann E, Thiefes A, Buhrow D, Dittrich-Breiholz O, Schneider H, Resch K,
Kracht M (2005) MEK1-dependent delayed expression of Fos-related antigen-1
counteracts c-Fos and p65 NF-kappaB-mediated interleukin-8 transcription in
response to cytokines or growth factors. J Biol Chem., 280(10):9706-18.
7. Bandman O, Coleman RT, Loring JF, Seilhamer JJ, Cocks BG (2002)
Complexity of inflammatory responses in endothelial cells and vascular smooth
muscle cells determined by microarray analysis. Ann N Y Acad Sci., 975:77-90.
8. Holzberg D, Knight CG, Dittrich-Breiholz O, Schneider H, Dörrie A, Hoffmann
E, Resch K, Kracht M (2003) Disruption of the c-JUN-JNK complex by a cell-
permeable peptide containing the c-JUN delta domain induces apoptosis and
affects a distinct set of interleukin-1-induced inflammatory genes. J Biol Chem.,
9. Keller M, Rüegg A, Werner S, Beer HD (2008) Active caspase-1 is a regulator of
unconventional protein secretion. Cell., 132(5):818-31.
11. Juffermans NP, Florquin S, Camoglio L, Verbon A, Kolk AH, Speelman P, van
Deventer SJ, van Der Poll T (2000) Interleukin-1 signaling is essential for host
defense during murine pulmonary tuberculosis. J Infect Dis.,182(3):902-8.
12. Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood.,
13. Vigers GP, Anderson LJ, Caffes P, Brandhuber BJ (1997) Crystal structure
of the type-I interleukin-1 receptor complexed with interleukin-1beta. Nature.,
14. Ordureau A, Smith H, Windheim M, Peggie M, Carrick E, Morrice N, Cohen
P (2008) The IRAK-catalysed activation of the E3 ligase function of Pellino
isoforms induces the Lys63-linked polyubiquitination of IRAK1. Biochem J.,
15. Wesche H, Korherr C, Kracht M, Falk W, Resch K, Martin MU (1997) The
interleukin-1 receptor accessory protein (IL-1RAcP) is essential for IL-1-
induced activation of interleukin-1 receptor-associated kinase (IRAK) and
stress-activated protein kinases (SAP kinases). J Biol Chem., 272(12):7727-31.
16. Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M (1999) Signaling by
proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient
for JNK and IKK activation and target gene induction via an amino-terminal
effector domain. Genes Dev., 13(10):1297-308.
17. Yao J, Kim TW, Qin J, Jiang Z, Qian Y, Xiao H, Lu Y, Qian W, Gulen MF,
Sizemore N, DiDonato J, Sato S, Akira S, Su B, Li X (2007) Interleukin-1 (IL-
1)-induced TAK1-dependent Versus MEKK3-dependent NFkappaB activation
pathways bifurcate at IL-1 receptor-associated kinase modification. J Biol
18. Krause A, Holtmann H, Eickemeier S, Winzen R, Szamel M, Resch K,
Saklatvala J, Kracht M (1998) Stress-activated protein kinase/Jun N-terminal
kinase is required for interleukin (IL)-1-induced IL-6 and IL-8 gene expression
in the human epidermal carcinoma cell line KB. J Biol Chem., 273(37):23681-9.
19. Finch A, Holland P, Cooper J, Saklatvala J, Kracht M (1997) Selective
activation of JNK/SAPK by interleukin-1 in rabbit liver is mediated by MKK7.
FEBS Lett., 418(1-2):144-8.
20. Finch A, Davis W, Carter WG, Saklatvala J (2001) Analysis of mitogen-
activated protein kinase pathways used by interleukin 1 in tissues in vivo:
activation of hepatic c-Jun N-terminal kinases 1 and 2, and mitogen-activated
protein kinase kinases 4 and 7. Biochem J., 353(Pt 2):275-81.
21. Hoffmann E, Ashouri J, Wolter S, Doerrie A, Dittrich-Breiholz O, Schneider
H, Wagner EF, Troppmair J, Mackman N, Kracht M (2008) Transcriptional
regulation of EGR-1 by the interleukin-1-JNK-MKK7-c-Jun pathway. J Biol
22. Hammaker DR, Boyle DL, Inoue T, Firestein GS (2007) Regulation of the JNK
pathway by TGF-beta activated kinase 1 in rheumatoid arthritis synoviocytes.
Arthritis Res Ther., 9(3):R57.
23. Freshney NW, Rawlinson L, Guesdon F, Jones E, Cowley S, Hsuan J,
Saklatvala J (1994) Interleukin-1 activates a novel protein kinase cascade that
results in the phosphorylation of Hsp27. Cell.,78(6):1039-49.
24. Cuenda A, Alonso G, Morrice N, Jones M, Meier R, Cohen P, Nebreda AR
(1996) Purification and cDNA cloning of SAPKK3, the major activator of RK/
p38 in stress- and cytokine-stimulated monocytes and epithelial cells. EMBO
25. Kracht M, Truong O, Totty NF, Shiroo M, Saklatvala J (1994) Interleukin 1
alpha activates two forms of p54 alpha mitogen-activated protein kinase in
rabbit liver. J Exp Med., 180(6):2017-25.
26. Cirillo G, Casalino L, Vallone D, Caracciolo A, De Cesare D, Verde P (1999)
Role of distinct mitogen-activated protein kinase pathways and cooperation
between Ets-2, ATF-2, and Jun family members in human urokinase-type
plasminogen activator gene induction by interleukin-1 and tetradecanoyl
phorbol acetate. Mol Cell Biol., 19(9):6240-52.
27. Morton S, Davis RJ, Cohen P (2004) Signalling pathways involved in multisite
phosphorylation of the transcription factor ATF-2. FEBS Lett., 572(1-3):177-83.
28. Weber A, Wasiliew P, Kracht M (2010) Interleukin-1 (IL-1) pathway. Sci
29. Dinarello CA (2005)The many worlds of reducing interleukin-1. Arthritis
30. Brissoni B, Agostini L, Kropf M, Martinon F, Swoboda V, Lippens S, Everett
H, Aebi N, Janssens S, Meylan E, Felberbaum-Corti M, Hirling H, Gruenberg
J, Tschopp J, Burns K (2006) Intracellular trafficking of interleukin-1 receptor
I requires Tollip. Curr Biol., 16(22):2265-70.
31. Burns K, Clatworthy J, Martin L, Martinon F, Plumpton C, Maschera B, Lewis
A, Ray K, Tschopp J, Volpe F (2000) Tollip, a new component of the IL-1RI
pathway, links IRAK to the IL-1 receptor. Nat Cell Biol.,2(6):346-51.
32. Didierlaurent A, Brissoni B, Velin D, Aebi N, Tardivel A, Käslin E, Sirard
JC, Angelov G, Tschopp J, Burns K (2006) Tollip regulates proinflammatory
responses to interleukin-1 and lipopolysaccharide. Mol Cell Biol., 26(3):735-42.
33. Mendoza H, Campbell DG, Burness K, Hastie J, Ronkina N, Shim JH, Arthur
JS, Davis RJ, Gaestel M, Johnson GL, Ghosh S, Cohen P (2008) Roles for TAB1
in regulating the IL-1-dependent phosphorylation of the TAB3 regulatory
subunit and activity of the TAK1 complex. Biochem J., 409(3):711-22.
34. Sun SC, Ganchi PA, Ballard DW, Greene WC (1993) NF-kappa B
controls expression of inhibitor I kappa B alpha: evidence for an inducible
autoregulatory pathway. Science., 259(5103):1912-5.
35. Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Dérijard B,
Davis RJ (1996) Selective interaction of JNK protein kinase isoforms with
transcription factors. EMBO J., 15(11):2760-70.
36. Toh ML, Yang Y, Leech M, Santos L, Morand EF (2004) Expression of
mitogen-activated protein kinase phosphatase 1, a negative regulator of the
mitogen-activated protein kinases, in rheumatoid arthritis: up-regulation by
interleukin-1beta and glucocorticoids. Arthritis Rheum., 50(10):3118-28.