IL36B

IL-36β (IL36B) is a pro-inflammatory cytokine of the IL-1 family that requires N-terminal proteolytic processing at a conserved A-X-Asp motif to attain full agonist activity, increasing potency by approximately 1,000–10,000-fold (PMID:21965679). The processed cytokine signals through a heterodimeric receptor comprising IL-1Rrp2 (IL-1RL2) and the co-receptor IL-1RAcP, activating NF-κB, JNK, ERK1/2, p38 MAPK, and Akt pathways to induce downstream mediators including IL-6, IL-8/CXCL8, antimicrobial peptides (β-defensins), matrix metalloproteinases, and multiple chemokines in keratinocytes, synovial fibroblasts, chondrocytes, and lung epithelial cells (PMID:14734551, PMID:21242515, PMID:28869889). IL-36Ra antagonizes IL-36β signaling by binding IL-1Rrp2 and preventing recruitment of IL-1RAcP, thereby blocking formation of the functional signaling complex (PMID:21965679). IL-36β also acts on monocytes and myeloid dendritic cells to promote their maturation and cytokine secretion, bridging innate and adaptive immune responses (PMID:24829417).

1. 2000 Medium

   Identification of IL36B as a novel IL-1 family member resolved whether additional cytokines with IL-1-like fold existed in the chromosome 2q cluster.

   Evidence cDNA cloning, sequence homology analysis, and protein structure modeling showing structural relatedness to IL-1β/IL-1Ra

   PMID:10625660

   Open questions at the time

   • No functional activity or receptor identified at this stage
   • Expression pattern beyond transcript detection unknown
2. 2001 Medium

   Demonstration that IL36B activates NF-κB specifically through the orphan receptor IL-1Rrp2 established its cognate receptor and distinguished it from classical IL-1 signaling.

   Evidence NF-κB-luciferase reporter assay with receptor panel screening in transfected cells

   PMID:11466363

   Open questions at the time

   • Whether a co-receptor is needed was not addressed
   • Signaling pathways beyond NF-κB not yet mapped
3. 2004 High

   Identification of IL-1RAcP as an essential co-receptor for IL-36β signaling completed the receptor complex architecture and revealed activation of both NF-κB and MAPK (JNK, ERK1/2) cascades.

   Evidence Anti-IL-1RAcP blocking antibodies, dominant-negative IL-1RAcP transfection, and NF-κB/IL-8 reporter assays in NCI/ADR-RES cells

   PMID:14734551

   Open questions at the time

   • Identity of the protease(s) activating the full-length precursor unknown
   • Structural basis for IL-1Rrp2/IL-1RAcP heterodimerization not resolved
4. 2006 Medium

   Demonstration that primary synovial fibroblasts and chondrocytes respond to IL-36β extended its functional relevance beyond skin to joint inflammation.

   Evidence Cytokine (IL-6, MMP) measurement by ELISA and receptor expression profiling in primary human joint cells

   PMID:16646978

   Open questions at the time

   • In vivo relevance in joint disease models not tested
   • Relative contribution of IL-36β versus other IL-36 family members in joints unclear
5. 2011 High

   Defining the N-terminal A-X-Asp processing requirement resolved a long-standing question about why recombinant full-length IL-36β showed weak activity, and co-IP experiments showed IL-36Ra antagonizes signaling by blocking IL-1RAcP recruitment to IL-1Rrp2.

   Evidence Systematic N-terminal truncation mutagenesis with NF-κB reporter dose-response and co-immunoprecipitation of receptor subunits

   PMID:21965679

   Open questions at the time

   • The endogenous protease(s) responsible for N-terminal cleavage in vivo remain unidentified
   • Whether processing occurs intracellularly or extracellularly is unknown
6. 2011 Medium

   Showing that IL-36β induces antimicrobial peptides (β-defensin-2, HBD-3) in reconstituted human epidermis established its role in cutaneous antimicrobial defense and placed it downstream of IL-1α/TNF-α signaling.

   Evidence qRT-PCR, immunohistochemistry, and secretion assays in 3D reconstituted human epidermis model

   PMID:21242515

   Open questions at the time

   • In vivo antimicrobial efficacy not demonstrated
   • Whether IL-36β acts on immune cells in skin besides keratinocytes not addressed
7. 2014 Medium

   Demonstrating that IL-36 cytokines activate monocytes and myeloid dendritic cells to promote T cell proliferation established IL-36β as a bridge between innate and adaptive immunity.

   Evidence Flow cytometry for surface markers, ELISA for cytokines, allogeneic CD4+ T cell proliferation assay, and intradermal injection mouse model

   PMID:24829417

   Open questions at the time

   • IL-36β-specific contributions were not always distinguished from other IL-36 isoforms
   • Whether dendritic cell activation requires processed IL-36β specifically was not tested
8. 2017 Medium

   Identification of p38 MAPK, ERK, and Akt as signaling mediators in lung fibroblasts and bronchial epithelial cells extended IL-36β activity to pulmonary tissue and broadened the known downstream signaling repertoire.

   Evidence Pharmacological inhibitors of p38MAPK, ERK, and Akt combined with qRT-PCR and ELISA in primary lung cells

   PMID:28869889

   Open questions at the time

   • IL-36 isoform-specific effects in lung were not fully resolved
   • In vivo pulmonary disease relevance not demonstrated

• The identity of the endogenous protease(s) that cleave IL-36β to its active form in vivo, the structural basis for the IL-36β/IL-1Rrp2/IL-1RAcP ternary complex, and IL-36β-specific (versus pan-IL-36) contributions in disease remain unresolved.
• Endogenous activating protease(s) not identified
• No crystal structure of IL-36β bound to its receptor complex
• IL-36β-specific versus redundant functions with IL-36α/γ not delineated in vivo