IL-1 signaling pathway (WP3271)

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). 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). 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, and to a lesser extent by other cell types such as epithelial cells endothelial cells and fibroblasts. IL-1 alpha, is a membrane anchored protein which signals through autocrine or juxtracrine mechanisms where as the soluble IL-1β acts in a paracrine or systemic manner. 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. 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. 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-κB through different signaling mechanisms. Two IL-1 receptor-associated kinases, IRAK-1 and IRAK-2 have been implicated in the activation of NF-κB. IRAK 1 and 2 functions as adapter proteins and protein kinases to transmit downstream signals. 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-κB-inducing kinase (NIK) to two I-kappaB kinases (IKK-1 and -2), leading to NF-kappaB activation. 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. The above mentioned signaling events co-operatively induce the expression of IL-1 target genes such as CCL2, IL-8 and IL-6. 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-1α and β, 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 signaling. 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. 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. Please access this pathway at [http://www.netpath.org/netslim/IL_1_pathway.html NetSlim] database. If you use this pathway, please cite the following paper: Kandasamy, K., Mohan, S. S., Raju, R., Keerthikumar, S., Kumar, G. S. S., Venugopal, A. K., Telikicherla, D., Navarro, J. D., Mathivanan, S., Pecquet, C., Gollapudi, S. K., Tattikota, S. G., Mohan, S., Padhukasahasram, H., Subbannayya, Y., Goel, R., Jacob, H. K. C., Zhong, J., Sekhar, R., Nanjappa, V., Balakrishnan, L., Subbaiah, R., Ramachandra, Y. L., Rahiman, B. A., Prasad, T. S. K., Lin, J., Houtman, J. C. D., Desiderio, S., Renauld, J., Constantinescu, S. N., Ohara, O., Hirano, T., Kubo, M., Singh, S., Khatri, P., Draghici, S., Bader, G. D., Sander, C., Leonard, W. J. and Pandey, A. (2010). NetPath: A public resource of curated signal transduction pathways. Genome Biology. 11:R3.
last edited

Authors

Mkutmon, MaintBot, and Egonw

Cited In

Organism

Bos taurus

Communities

Annotations

Pathway Ontology: interleukin-1 signaling pathway Interleukin mediated signaling pathway interleukin-1 signaling pathway signaling pathway in the adaptive immune response

Participants

Label Type Compact Identifier
UBE2N Protein ensembl:ENSBTAG00000021767
MAP3K2 Protein ensembl:ENSBTAG00000004216
REL Protein ensembl:ENSBTAG00000015386
HSPB2 Protein None
MAPK3 Protein ensembl:ENSBTAG00000016156
IKBKB Protein ensembl:ENSBTAG00000007599
PRKCZ Protein ensembl:ENSBTAG00000014119
Ca 2+ Metabolite hmdb:HMDB0000464
TAB2 Protein ensembl:ENSBTAG00000013454
MAP3K14 Protein ensembl:ENSBTAG00000007084
MAP2K2 Protein ensembl:ENSBTAG00000024450
PIK3R2 Protein None
TRAF6 Protein ensembl:ENSBTAG00000036009
MYD88 Protein ensembl:ENSBTAG00000000563
TOLLIP Protein ensembl:ENSBTAG00000008237
TOLLIP Protein ensembl:ENSBTAG00000008237
ECSIT Protein ensembl:ENSBTAG00000015049
SQSTM1 Protein ensembl:ENSBTAG00000015591
CHUK Protein ensembl:ENSBTAG00000007591
NFKBIB Protein ensembl:ENSBTAG00000001778
RELA Protein ensembl:ENSBTAG00000013895
MAPK14 Protein ensembl:ENSBTAG00000020783
CCL2 Rna ensembl:ENSBTAG00000037811
BIKBA Protein ensembl:ENSBTAG00000016683
NFKB1 Protein ensembl:ENSBTAG00000020270
AKT1 Protein ensembl:ENSBTAG00000017636
NFKB1 Protein ensembl:ENSBTAG00000020270
TRAF6 Protein ensembl:ENSBTAG00000036009
PIK3R1 Protein ensembl:ENSBTAG00000010989
MAP2K3 Protein ensembl:ENSBTAG00000010576
TRAF6 Protein ensembl:ENSBTAG00000036009
PELI1 Protein ensembl:ENSBTAG00000020865
IKBKG Protein ensembl:ENSBTAG00000006268
MYD88 Protein ensembl:ENSBTAG00000000563
PTPN11 Protein ensembl:ENSBTAG00000002048
MAPKAPK2 Protein ensembl:ENSBTAG00000038107
MAPK1 Protein ensembl:ENSBTAG00000010312
RELA Protein ensembl:ENSBTAG00000013895
MAP2K1 Protein ensembl:ENSBTAG00000033983
PLCG1 Protein ensembl:ENSBTAG00000017584
TRAF6 Protein ensembl:ENSBTAG00000036009
IL1A Protein ensembl:ENSBTAG00000010349
TAB3 Protein ensembl:ENSBTAG00000048159
MAP2K6 Protein ensembl:ENSBTAG00000001609
UBE2V1 Protein None
IL1RAP Protein ensembl:ENSBTAG00000013205
IL1B Protein ensembl:ENSBTAG00000001321
REL Protein ensembl:ENSBTAG00000015386
MAPK8 Protein ensembl:ENSBTAG00000007876
IL1R1 Protein ensembl:ENSBTAG00000005273
MAPK9 Protein ensembl:ENSBTAG00000004709
IL1RAP Protein ensembl:ENSBTAG00000013205
PELI2 Protein ensembl:ENSBTAG00000005141
MAP3K1 Protein ensembl:ENSBTAG00000013790
MAP2K7 Protein ensembl:ENSBTAG00000010639
MAP3K3 Protein ensembl:ENSBTAG00000008151
MAP3K7IP1 Protein ensembl:ENSBTAG00000019828
MAP2K4 Protein ensembl:ENSBTAG00000012103
TRAF6 Protein ensembl:ENSBTAG00000036009
IKBKG Protein ensembl:ENSBTAG00000006268
IL1R1 Protein ensembl:ENSBTAG00000005273
IRAK4 Protein ensembl:ENSBTAG00000021105
IRAK1 Protein ensembl:ENSBTAG00000016085
IRAKM Protein ensembl:ENSBTAG00000007636
IRAK2 Protein ensembl:ENSBTAG00000006193
MAP3K7 Protein ensembl:ENSBTAG00000002625
MAPK14 Protein ensembl:ENSBTAG00000020783
JUN Protein ensembl:ENSBTAG00000004037
ATF2 Protein ensembl:ENSBTAG00000002295
MAPK9 Protein ensembl:ENSBTAG00000004709
MAPK8 Protein ensembl:ENSBTAG00000007876

References

  1. Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GSS, Venugopal AK, et al. NetPath: a public resource of curated signal transduction pathways. Genome Biol. 2010 Jan 12;11(1):R3. PubMed Europe PMC Scholia