IL-1 Family Signaling Pathways

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

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
Transcriptional Regulation
Transcriptional Regulation
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
Pro-inflammatory
IL-1 Inhibitors
IL-1ra
IL-1 alpha
IL-1 beta
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IL-1 RI
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IL-1 RAcP
Anti-inflammatory
IL-1 Signaling
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
Pro-inflammatory
IL-18 Inhibitors
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
Pro-inflammatory
IL-33 Inhibitors
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
Pro-inflammatory
IL-36 Inhibitors
IL-36Ra
IL-36 alpha
IL-36 beta
IL-36 gamma
IL-1 RAcP
IL-1 Rrp2
Anti-inflammatory
IL-36 Signaling
Anti-inflammatory
Anti-inflammatory

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

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

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

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

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

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

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

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

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.