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IL-1 Family Signaling Pathways

Click on one of the IL-1 family cytokines shown in the Explore Pathways box below to highlight the signaling pathway and overall effect induced by each cytokine along with the intrinsic inhibitors that may alter its activity.

IL-1 Family Signaling Pathways
IL-1ra
IL-1ra
IL-1 alpha
IL-1 beta
IL-1 alpha
IL-1 beta
IL-18
IL-18
IL-18 BP
IL-18 BP
IL-37
IL-37
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IL-33
IL-33
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IL-36Ra
IL-36Ra
IL-36 alpha
IL-36 beta
IL-36 gamma
IL-36 alpha
IL-36 beta
IL-36 gamma
IL-38
IL-38
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IL-1 RI
IL-1 RI
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IL-1 RAcP
IL-1 RAcP
IL-18 R alpha
IL-18 R alpha
IL-18 R beta
IL-18 R beta
IL-18 R alpha
IL-18 R alpha
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ST2/IL-1 R4
ST2/IL-1 R4
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IL-1 RAcP
IL-1 RAcP
IL-1 Rrp2
IL-1 Rrp2
IL-1 RAcP
IL-1 RAcP
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Soluble
IL-1 RI
Soluble
IL-1 RI
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IL-1 Rrp2
IL-1 Rrp2
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MyD88
MyD88
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MyD88
MyD88
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MyD88
MyD88
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IRAK4
IRAK4
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IRAK1/2
IRAK1/2
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TRAF-6
TRAF-6
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TAB1/2
TAB1/2
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TAK1
TAK1
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TRAF-6
TRAF-6
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IKK
IKK
I kappa B
I kappa B
I kappa B
I kappa B
Proteasome
Proteasome
NF-kappa B
NF-kappa B
NF-kappa B
NF-kappa B
MKK
MKK
p38
p38
JNK
JNK
AP-1
AP-1
JNK
JNK
AP-1
AP-1
IKK
IKK
I kappa B
I kappa B
I kappa B
I kappa B
Proteasome
Proteasome
NF-kappa B
NF-kappa B
NF-kappa B
NF-kappa B
ERK1/2
ERK1/2
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Pro-IL-33
Pro-IL-33
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IL-37
IL-37
Pro-IL-1 alpha
Pro-IL-1 alpha
Pro-inflammatory Response
Pro-inflammatory Response
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Transcriptional Regulation
Transcriptional Regulation
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IL-1ra
IL-1 alpha
IL-1 beta
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IL-1 RI
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IL-1 RAcP
IL-1 alpha
IL-1 beta
IL-1 RAcP
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IL-1 RII
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IL-1 alpha
IL-1 beta
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IL-1 RI
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SIGIRR
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IL-1 alpha
IL-1 beta
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IL-1 RI
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Soluble
IL-1 RAcP
IL-1 alpha
IL-1 beta
IL-1 RAcP
Soluble
IL-1 RI or RII
IL-1 Signaling
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Pro-inflammatory
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IL-1 Inhibitors
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IL-1ra
IL-1 alpha
IL-1 beta
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IL-1 RI
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IL-1 RAcP
Anti-inflammatory
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IL-1 Signaling
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IL-18
Soluble
IL-18 R alpha
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SIGIRR
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IL-18
IL-18 R alpha
IL-18 R beta
IL-18 Signaling
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Pro-inflammatory
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IL-18 Inhibitors
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IL-33
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SIGIRR
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ST2/IL-1 R4
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IL-33
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Soluble
ST2/IL-1 R4
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IL-33 Signaling
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Pro-inflammatory
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IL-33 Inhibitors
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IL-36Ra
IL-36 alpha
IL-36 beta
IL-36 gamma
IL-1 RAcP
IL-1 Rrp2
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SIGIRR
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IL-36 Signaling
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Pro-inflammatory
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IL-36 Inhibitors
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IL-36Ra
IL-36 alpha
IL-36 beta
IL-36 gamma
IL-1 RAcP
IL-1 Rrp2
Anti-inflammatory
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IL-36 Signaling
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Anti-inflammatory
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Anti-inflammatory
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IL-1 Inhibitor

IL-1ra
An IL-1 family cytokine that acts as an IL-1 receptor antagonist by preventing IL-1 alpha or IL-1 beta from binding to IL-1 RI; Binding of IL-1ra to IL-1 RI inhibits recruitment of IL-1 RAcP and downstream signaling
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IL-1 Inhibitors

IL-1ra
An IL-1 family cytokine that acts as an IL-1 receptor antagonist by preventing IL-1 alpha or IL-1 beta from binding to IL-1 RI; Binding of IL-1ra to IL-1 RI inhibits recruitment of IL-1 RAcP and downstream signaling
IL-1 RII
An IL-1 decoy receptor with a short cytoplasmic domain that is incapable of transducing an IL-1 signal
SIGIRR/TIR8
Single immunoglobulin domain containing IL-1 receptor -related (SIGIRR) molecule; A subtype of the IL-1 R family that contains a single extracellular immunoglobulin-like domain and may inhibit signaling by IL-1 family cytokines in a context-dependent manner
Soluble IL-1 RAcP
A soluble receptor that can bind to IL-1 - IL-1 RI but is incapable of propagating a signal; Enhances IL-1 binding to soluble IL-1 RII
Soluble IL-1 RI or RII
Soluble receptors that can bind to IL-1 and IL-1 RAcP but are incapable of propagating a signal
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IL-18 Inhibitors

IL-18 BP
IL-18 binding protein (IL-18 BP); A soluble protein that binds to IL-18 with higher affinity than either the cell bound or soluble forms of IL-18 R and prevents IL-18 signaling
SIGIRR/TIR8
Single immunoglobulin domain containing IL-1 receptor-related (SIGIRR) molecule; A subtype of the IL-1 R family that contains a single extracellular immunoglobulin-like domain and may inhibit signaling by IL-1 family cytokines in a context-dependent manner
Soluble IL-18 R alpha
A soluble receptor that can bind to IL-18 but is incapable of propagating a signal; A weak inhibitor compared to IL-18 BP
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IL-33 Inhibitors

SIGIRR/TIR8
Single immunoglobulin domain containing IL-1 receptor-related (SIGIRR) molecule; A subtype of the IL-1 R family that contains a single extracellular immunoglobulin-like domain and may inhibit signaling by IL-1 family cytokines in a context-dependent manner
Soluble ST2/IL-1 R4
A soluble receptor that can bind to IL-33 but is incapable of propagating a signal
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IL-36 Inhibitors

IL-36Ra
An IL-1 family cytokine that acts as an IL-36 receptor antagonist by preventing IL-36 alpha, IL-36 beta, or IL-36 gamma from binding to IL-1 Rrp2; Binding of IL-36Ra to IL-1 Rrp2 inhibits recruitment of IL-1 RAcP and downstream signaling
SIGIRR/TIR8
Single immunoglobulin domain containing IL-1 receptor-related (SIGIRR) molecule; A subtype of the IL-1 R family that contains a single extracellular immunoglobulin-like domain and may inhibit signaling by IL-1 family cytokines in a context-dependent manner
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IL-36 Inhibitor

IL-36Ra
An IL-1 family cytokine that acts as an IL-36 receptor antagonist by preventing IL-36 alpha, IL-36 beta, or IL-36 gamma from binding to IL-1 Rrp2; Binding of IL-36Ra to IL-1 Rrp2 inhibits recruitment of IL-1 RAcP and downstream signaling
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Effects of IL-37

IL-37b: The longest of five isoforms of IL-37; both the immature and mature forms bind to IL-18 BP and enhance its ability to inhibit IL-18 activity; IL-37b also binds to IL-18 R alpha but does not act as a direct agonist or antagonist of IL-18 signaling; IL-37b can translocate to the nucleus where it may act as a transcriptional regulatlor
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Effects of IL-38

Binds to soluble IL-1 RI and IL-1 Rrp2; Binding of IL-38 to IL-1 Rrp2 may have anti-inflammatory effects similar to those induced by IL-36Ra
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IL-1 Family Signaling Pathways

 

Overview of the IL-1 Family Signaling Pathway

The IL-1 cytokine family consists of eleven members that play important roles in regulating inflammation. Members include IL-1 alpha, IL-1 beta, IL-1ra, IL-18, IL-33, IL-36Ra, IL-36 alpha, IL-36 beta, IL-36 gamma, IL-37, and IL-38. While most of these cytokines are biologically active as full-length molecules, activation and secretion of IL-1 beta and IL-18 requires inflammasome/Caspase-1-dependent processing. Other IL-1 family cytokines do not require Caspase-1 cleavage for activation but may undergo some form of protease processing since more potent forms of many of these cytokines can be generated by trimming amino acids at their N-terminal ends.

IL-1 family cytokines mediate their effects by binding to a primary IL-1 family receptor subunit, such as IL-1 RI, IL-18 R alpha, IL-1 Rrp2, or ST2, which subsequently recruits an accessory receptor, IL-1 RAcP or IL-18 R beta, to activate downstream signaling. IL-1 alpha, IL-1 beta, IL-18, IL-33, IL-36 alpha, IL-36 beta, and IL-36 gamma trigger intracellular signaling cascades that induce the NF-kappa B- and AP-1-dependent expression of pro-inflammatory cytokines, chemokines, and secondary mediators of the inflammatory response. In addition, unprocessed forms of IL-1 alpha and IL-33 and the mature form of IL-37b can translocate to the nucleus where they may act as transcriptional regulators. In contrast to the pro-inflammatory members of the IL-1 family, IL-1ra, IL-36Ra, IL-37, and IL-38 have anti-inflammatory effects. IL-1ra antagonizes IL-1 activity by binding to IL-1 RI. This prevents IL-1 alpha and IL-1 beta from interacting with their primary receptor subunit and inhibits recruitment of IL-1 RAcP. Similarly, IL-36Ra binds to IL-1 Rrp2 and inhibits IL-36 signaling. Less is known about IL-37 and IL-38, but both have also been suggested to have anti-inflammatory effects. Five splice variants of IL-37 (IL-37a-e) exist with four containing a putative Caspase-1 cleavage site. Both the immature and mature forms of the longest isoform, IL-37b, bind to IL-18 binding protein (IL-18 BP) and enhance its ability to inhibit IL-18 activity. IL-38 binds to the IL-36 receptor, IL-1 Rrp2, and soluble IL-1 RI. Initial data suggests that the interaction between IL-38 and IL-1 Rrp2 has anti-inflammatory effects similar to those induced by IL-36Ra.

In addition to IL-1ra and IL-36Ra, the pro-inflammatory effects of IL-1, IL-18, IL-33, and IL-36 are regulated by several other endogenous inhibitors. IL-I RII is an IL-1 family receptor that, unlike other receptors in this family, lacks a TIR domain. It can bind to IL-1 alpha and IL-1 beta and recruit IL-1 RAcP, but it is incapable of transducing a signal. As a result, it acts as an IL-1 decoy receptor. Soluble IL-1 RI and IL-I RII can also bind to IL-1 alpha and IL-1 beta and recruit IL-1 RAcP but cannot activate intracellular signaling. Similarly, soluble ST-2/IL-1 R4 and soluble IL-18 R alpha have been shown to negatively regulate IL-33 and IL-18 signaling, respectively. IL-18 signaling is also regulated by IL-18 BP. IL-18 BP is a soluble protein that binds to IL-18 with higher affinity than either the cell-bound or soluble forms of IL-18 R and prevents IL-18 signaling. Single immunoglobulin domain containing IL-1 receptor-related (SIGIRR) molecule is another potential endogenous inhibitor of IL-1, IL-18, IL-33, and IL-36 signaling. SIGIRR is a transmembrane protein with one extracellular Ig-like domain that has been shown to bind to several IL-1 family cytokines and inhibit signaling in a context-dependent manner.

To learn more, please visit our IL-1 Family Research Area.

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