IL1 signaling (WP195)

Homo sapiens

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 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.

Authors

Akhilesh Pandey , Axel Weber , Kristina Hanspers , Martijn Van Iersel , NetPath , Christine Chichester , Joppe014 , Zahra Roudbari , Martina Summer-Kutmon , Lauren J. Dupuis , Egon Willighagen , and Eric Weitz

Activity

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Organisms

Homo sapiens

Communities

CPTAC PancCanNet

Annotations

Pathway Ontology

interleukin-1 signaling pathway Interleukin mediated signaling pathway signaling pathway in the adaptive immune response oxidative phosphorylation pathway

Participants

Label Type Compact URI Comment
Ca 2+ Metabolite hmdb:HMDB0000464
UBE2N Protein ncbigene:7334
MAP3K2 Protein ncbigene:10746
REL Protein ncbigene:5966
HSPB2 Protein ncbigene:3316
MAPK3 Protein ncbigene:5595
IKBKB Protein ncbigene:3551
PRKCZ Protein ncbigene:5590
TAB2 Protein ncbigene:23118
MAP3K14 Protein ensembl:ENSG00000006062
MAP2K2 Protein ncbigene:5605
PIK3R2 Protein ncbigene:5296
TRAF6 Protein ncbigene:7189
MYD88 Protein ncbigene:4615
TOLLIP Protein ncbigene:54472
ECSIT Protein ncbigene:51295
SQSTM1 Protein ncbigene:8878
CHUK Protein ncbigene:1147
NFKBIB Protein ncbigene:4793
RELA Protein ncbigene:5970
MAPK14 Protein ncbigene:1432
NFKBIA Protein ncbigene:4792
NFKB1 Protein ncbigene:4790
AKT1 Protein ncbigene:207
PIK3R1 Protein ncbigene:5295
MAP2K3 Protein ncbigene:5606
PELI1 Protein ncbigene:57162
IKBKG Protein ncbigene:8517
PTPN11 Protein ncbigene:5781
MAPKAPK2 Protein ncbigene:9261
MAPK1 Protein ncbigene:5594
MAP2K1 Protein ncbigene:5604
PLCG1 Protein ncbigene:5335
IL1A Protein ncbigene:3552
TAB3 Protein ncbigene:257397
MAP2K6 Protein ncbigene:5608
UBE2V1 Protein ncbigene:7335
IL1RAP Protein ncbigene:3556
IL1B Protein ncbigene:3553
MAPK8 Protein ncbigene:5599
IL1R1 Protein ncbigene:3554
MAPK9 Protein ncbigene:5601
PELI2 Protein ncbigene:57161
MAP3K1 Protein ncbigene:4214
MAP2K7 Protein ncbigene:5609
MAP3K3 Protein ncbigene:4215
TAB1 Protein ncbigene:10454
MAP2K4 Protein ncbigene:6416
IRAK4 Protein ncbigene:51135
IRAK1 Protein ncbigene:3654
IRAK3 Protein ncbigene:11213
IRAK2 Protein ncbigene:3656
MAP3K7 Protein ncbigene:6885
JUN Protein ncbigene:3725
ATF2 Protein ncbigene:1386

References

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