IL-1 signaling pathway (WP3271)

Bos taurus

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.

Authors

Martina Summer-Kutmon and Egon Willighagen

Activity

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Organisms

Bos taurus

Communities

Annotations

Pathway Ontology

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

Participants

Label Type Compact URI Comment
Ca 2+ Metabolite hmdb:HMDB0000464
UBE2N Protein ensembl:ENSBTAG00000021767 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7334
MAP3K2 Protein ensembl:ENSBTAG00000004216 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10746
REL Protein ensembl:ENSBTAG00000015386 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5966
MAPK3 Protein ensembl:ENSBTAG00000016156 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5595
IKBKB Protein ensembl:ENSBTAG00000007599 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3551
PRKCZ Protein ensembl:ENSBTAG00000014119 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5590
TAB2 Protein ensembl:ENSBTAG00000013454 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:23118
MAP3K14 Protein ensembl:ENSBTAG00000007084 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000006062
MAP2K2 Protein ensembl:ENSBTAG00000024450 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5605
TRAF6 Protein ensembl:ENSBTAG00000036009 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7189
MYD88 Protein ensembl:ENSBTAG00000000563 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4615
TOLLIP Protein ensembl:ENSBTAG00000008237 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:54472
ECSIT Protein ensembl:ENSBTAG00000015049 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:51295
SQSTM1 Protein ensembl:ENSBTAG00000015591 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8878
CHUK Protein ensembl:ENSBTAG00000007591 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1147
NFKBIB Protein ensembl:ENSBTAG00000001778 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4793
RELA Protein ensembl:ENSBTAG00000013895 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5970
MAPK14 Protein ensembl:ENSBTAG00000020783 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1432
BIKBA Protein ensembl:ENSBTAG00000016683 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4792
NFKB1 Protein ensembl:ENSBTAG00000020270 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4790
AKT1 Protein ensembl:ENSBTAG00000017636 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:207
PIK3R1 Protein ensembl:ENSBTAG00000010989 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5295
MAP2K3 Protein ensembl:ENSBTAG00000010576 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5606
PELI1 Protein ensembl:ENSBTAG00000020865 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:57162
IKBKG Protein ensembl:ENSBTAG00000006268 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8517
PTPN11 Protein ensembl:ENSBTAG00000002048 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5781
MAPKAPK2 Protein ensembl:ENSBTAG00000038107 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9261
MAPK1 Protein ensembl:ENSBTAG00000010312 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5594
MAP2K1 Protein ensembl:ENSBTAG00000033983 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5604
PLCG1 Protein ensembl:ENSBTAG00000017584 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5335
IL1A Protein ensembl:ENSBTAG00000010349 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3552
TAB3 Protein ensembl:ENSBTAG00000048159 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:257397
MAP2K6 Protein ensembl:ENSBTAG00000001609 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5608
IL1RAP Protein ensembl:ENSBTAG00000013205 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3556
IL1B Protein ensembl:ENSBTAG00000001321 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3553
MAPK8 Protein ensembl:ENSBTAG00000007876 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5599
IL1R1 Protein ensembl:ENSBTAG00000005273 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3554
MAPK9 Protein ensembl:ENSBTAG00000004709 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5601
PELI2 Protein ensembl:ENSBTAG00000005141 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:57161
MAP3K1 Protein ensembl:ENSBTAG00000013790 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4214
MAP2K7 Protein ensembl:ENSBTAG00000010639 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5609
MAP3K3 Protein ensembl:ENSBTAG00000008151 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4215
MAP3K7IP1 Protein ensembl:ENSBTAG00000019828 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10454
MAP2K4 Protein ensembl:ENSBTAG00000012103 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6416
IRAK4 Protein ensembl:ENSBTAG00000021105 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:51135
IRAK1 Protein ensembl:ENSBTAG00000016085 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3654
IRAKM Protein ensembl:ENSBTAG00000007636 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:11213
IRAK2 Protein ensembl:ENSBTAG00000006193 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3656
MAP3K7 Protein ensembl:ENSBTAG00000002625 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6885
JUN Protein ensembl:ENSBTAG00000004037 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3725
ATF2 Protein ensembl:ENSBTAG00000002295 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L: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