IL36G

IL-36γ (IL-1F9) is a pro-inflammatory IL-1 family cytokine that signals through the IL-1Rrp2 (IL-1R6)/IL-1RAcP heterodimeric receptor complex to activate NF-κB and MAPKs (JNK, ERK1/2), thereby driving neutrophil chemokine production, dendritic cell maturation, macrophage pyroptosis via NLRP3 inflammasome engagement, and cancer-associated skeletal muscle wasting (PMID:14734551, PMID:20870894, PMID:22144259, PMID:41889065, PMID:39266531). Its transcription in myeloid cells is directly controlled by T-bet and NF-κB, while epithelial expression is suppressed by active vitamin D3 through VDR signaling and inversely regulated by PCSK9 in keratinocytes (PMID:23095752, PMID:38085113, PMID:35862195). IL-36γ is released from bronchial epithelial cells upon TLR3 stimulation and accumulates intracellularly in keratinocytes after mechanical injury, and it acts in a paracrine fashion on fibroblasts and dendritic cells to amplify inflammatory cascades including IL-8, CXCL3, and CCL20 induction (PMID:20870894, PMID:31010609, PMID:23095752). In advanced cancer, a TLR4-induced neutrophil-like monocyte subset expressing IL-36γ drives cachexia, and genetic inhibition of IL-36γ signaling rescues muscle wasting in vivo (PMID:39266531).

1. 2003 Medium

   Testing whether IL-36γ activates classical IL-1-type neuroinflammatory signaling revealed that, despite receptor expression on glia, IL-36γ fails to activate NF-κB, MAPKs, or induce IL-6 in brain glial cells or elicit sickness behaviors in vivo, establishing that its signaling is cell-type restricted.

   Evidence NF-κB and MAPK assays in primary astrocytes/microglia, IL-6 ELISA, intracerebroventricular injection in rats

   PMID:12799018

   Open questions at the time

   • Findings are entirely negative; alternative signaling pathways in glia not tested
   • No positive-control cell type included for comparison
2. 2004 High

   Defining the receptor and signaling requirements for IL-36γ established that it signals through IL-1Rrp2 (IL-1R6) as its primary receptor and IL-1RAcP as an obligate co-receptor to activate NF-κB and MAPKs (JNK, ERK1/2), placing it firmly within the IL-1 signaling paradigm.

   Evidence NF-κB reporter assays, antibody blocking of IL-1Rrp2 and IL-1RAcP, dominant-negative IL-1RAcP transfection, MAPK phosphorylation in Jurkat and NCI/ADR-RES cells

   PMID:14734551

   Open questions at the time

   • Structural basis of IL-36γ–IL-1Rrp2 interaction not resolved
   • Signaling events downstream of MAPKs not characterized
3. 2010 High

   Demonstrating that TLR3-stimulated bronchial epithelial cells secrete IL-36γ, which then acts on lung fibroblasts to induce neutrophil chemokines (IL-8, CXCL3) and CCL20, established the epithelium-to-mesenchyme paracrine circuit through which IL-36γ promotes neutrophilic airway inflammation.

   Evidence IL-1F9 ELISA on epithelial supernatants, RT-PCR for IL-1Rrp2 on fibroblasts, chemokine induction assays in primary human lung fibroblasts

   PMID:20870894

   Open questions at the time

   • In vivo contribution to airway neutrophilia not demonstrated
   • Processing protease responsible for generating active IL-36γ in this context unknown
4. 2012 High

   Identifying T-bet and NF-κB as direct transcriptional regulators of IL-36γ in myeloid cells, and showing that mature IL-36γ induces an inflammatory gene program (TNFα, CCL20, S100A7, iNOS, and IL-36γ itself) in keratinocytes, revealed a feed-forward amplification loop linking innate immune activation to epithelial inflammation.

   Evidence T-bet siRNA knockdown, T-bet KO mice, ectopic T-bet expression, promoter analysis identifying T-bet and κB sites, IL-36γ stimulation of primary keratinocytes with mRNA profiling

   PMID:23095752

   Open questions at the time

   • Relative contributions of T-bet versus NF-κB to IL-36γ transcription in disease states not quantified
   • Feed-forward loop not tested in vivo
5. 2012 Medium

   Showing that IL-1Rrp2 expression within the myelomonocytic lineage is restricted to dendritic cells and that IL-36γ induces DC maturation markers (HLA-DR, CD83) defined DCs as key immune effectors of IL-36γ signaling.

   Evidence Flow cytometry for IL-1Rrp2 across myelomonocytic subsets, IL-36γ stimulation of monocyte-derived DCs with surface marker and cytokine readouts

   PMID:22144259

   Open questions at the time

   • Whether IL-36γ-matured DCs skew specific T-helper responses not resolved
   • Single lab; receptor restriction not confirmed in tissue-resident DC subsets
6. 2019 Medium

   Demonstrating that mechanical injury selectively upregulates intracellular IL-36γ protein in keratinocytes without extracellular secretion established that IL-36γ can function as a damage-associated intracellular signal in skin.

   Evidence qRT-PCR, ELISA, Western blot of scratch-wounded human keratinocyte monolayers

   PMID:31010609

   Open questions at the time

   • No intracellular binding partners or signaling role identified
   • Mechanism of non-conventional secretion or release upon cell death not tested
7. 2022 Medium

   Identifying PCSK9 as a negative regulator of IL-36γ expression in keratinocytes — validated by both siRNA knockdown and a human loss-of-function PCSK9 SNP — linked lipid metabolism regulators to IL-36γ-driven skin inflammation.

   Evidence PCSK9 siRNA in keratinocytes with RT-PCR/RNA-Seq, scRNA-Seq, IHC, genotyping of PCSK9 rs662145 in human skin

   PMID:35862195

   Open questions at the time

   • Mechanism by which PCSK9 represses IL36G transcription unknown
   • Whether PCSK9-mediated regulation operates outside the skin not tested
8. 2022 Medium

   Demonstrating that IL-36γ activates ERK1/2 and promotes colony formation, migration, and invasion of gastric cancer cells — effects blocked by IL-36RA — extended IL-36γ's functional repertoire to receptor-dependent pro-neoplastic signaling.

   Evidence ERK1/2 Western blot, colony formation, migration/invasion assays with IL-36RA inhibition in AGS, MKN1, MKN45 gastric cancer lines

   PMID:35512531

   Open questions at the time

   • In vivo tumor-promoting role not tested
   • Downstream transcriptional program mediating pro-neoplastic effects unknown
9. 2024 High

   Discovering that a TLR4-induced neutrophil-like monocyte subset (CiMs) expressing IL-36γ drives skeletal muscle wasting in cancer cachexia — with genetic inhibition of IL-36γ rescuing muscle loss in vivo — established IL-36γ as a causal effector of cancer-associated cachexia.

   Evidence Transcriptomics of monocyte subsets, in vivo genetic inhibition of IL-36γ signaling in advanced cancer mouse models with muscle mass measurements

   PMID:39266531

   Open questions at the time

   • Direct target cells and receptor on muscle not identified
   • Whether IL-36γ acts directly on myocytes or through intermediary signals not resolved
10. 2024 Medium

    Showing that active vitamin D3 suppresses IL-36γ production in nasal epithelial cells and that impaired local vitamin D conversion (reduced CYP27B1) elevates IL-36γ in nasal polyps established a VDR-dependent suppressive circuit that, when disrupted, promotes neutrophilic upper airway inflammation.

    Evidence CYP27B1 siRNA in HNECs, 1,25VD3 treatment with IL-36γ ELISA, RNA-Seq, nasal polyp tissue explants

    PMID:38085113

    Open questions at the time

    • Whether VDR directly binds the IL36G promoter not shown
    • Relevance to other mucosal sites not tested
11. 2026 Medium

    Demonstrating that IL-36γ drives macrophage pyroptosis through NF-κB-dependent NLRP3 inflammasome activation — confirmed by NF-κB inhibitor blockade and improved survival in IL-36G knockout sepsis models — established IL-36γ as a proximal trigger of inflammasome-mediated cell death in sepsis-related lung injury.

    Evidence IL-36G overexpression/knockdown in RAW264.7, NF-κB inhibitor BAY 11-7085, IL-36G KO mice in cecal ligation and puncture model with lung injury and survival readouts

    PMID:41889065

    Open questions at the time

    • Single lab, newly published, awaits independent confirmation
    • Whether IL-36γ directly primes or activates NLRP3 versus acting through transcriptional upregulation not fully dissected

• Key unresolved questions include the identity of the protease(s) that generate active IL-36γ in vivo in different tissues, the structural basis of IL-36γ–IL-1Rrp2–IL-1RAcP complex assembly, and whether IL-36γ has intracellular signaling functions independent of its cell-surface receptor.
• Activating protease identity remains unknown for most tissue contexts
• No crystal structure of the ternary signaling complex
• Intracellular accumulation without secretion (keratinocyte injury) has no known functional consequence