Interleukin-4
Interleukin-4 (IL-4) is a pleiotropic cytokine produced primarily by Th2 lymphocytes, mast cells, basophils, and innate lymphoid cells type 2 (ILC2s), and the principal initiating signal of type 2 immune responses. Its upstream role is to drive the differentiation of naïve helper T cells into Th2 cells – a positive feedback loop in which IL-4 promotes the very cell population that produces more IL-4, amplifying the type 2 response. It also drives B cell IgE class switching, directly linking the Th2 cytokine environment to the elevated IgE and atopic sensitisation characteristic of atopic dermatitis and allergic conditions more broadly. [4]
Receptor Signalling and Skin Barrier Suppression
IL-4 signals through two receptor complexes with different cellular distributions. The type I receptor – IL-4Rα paired with the common gamma chain (γc) – is expressed predominantly on haematopoietic cells including lymphocytes and drives the immunological arm of IL-4 signalling. The type II receptor – IL-4Rα paired with IL-13Rα1 – is expressed on non-haematopoietic cells including keratinocytes, and is the receptor through which IL-4 exerts its barrier-disrupting effects on skin tissue. Both receptor types signal via JAK kinases activating STAT6, which then acts as a transcription factor altering the expression of barrier-related genes. [2]
In keratinocytes, STAT6 activation by IL-4 downregulates multiple genes in the epidermal differentiation complex, including filaggrin (FLG), loricrin, and involucrin, and suppresses serine palmitoyltransferase (SPT), the rate-limiting enzyme initiating de novo ceramide synthesis. Reduced filaggrin impairs the natural moisturising factor pool and the corneocyte protein scaffold; reduced SPT activity directly reduces ceramide output, compromising the lamellar lipid architecture of the stratum corneum. These effects occur even in keratinocytes without underlying filaggrin gene mutations, IL-4 alone is sufficient to produce filaggrin suppression. The result is increased transepidermal water loss (TEWL), disrupted barrier integrity, and a permeable skin surface that allows allergen penetration and microbial colonisation. [1]
IL-4 in the Atopic Dermatitis Feedback Loop
IL-4’s role in atopic dermatitis is both initiating and self-amplifying. The type 2 cytokine environment IL-4 establishes promotes barrier disruption; barrier disruption allows allergen entry; allergen entry drives further Th2 activation and more IL-4 release – a closed loop in which the immune response and structural failure of the barrier reinforce each other. IL-4 is also the upstream driver of IL-13 production by Th2 cells, meaning much of the sustained tissue-level barrier damage in established atopic dermatitis is downstream of the IL-4 initiated Th2 response. Dupilumab blocks IL-4Rα, simultaneously inhibiting both IL-4 and IL-13 signalling through their shared receptor subunit, its clinical efficacy confirms that this axis is not merely associated with AD pathology but causally central to it. [3]
References
Chatzigeorgiou I, Koumaki D, Vakirlis E, et al. (2024). Restoration of Skin Barrier Abnormalities with IL4/13 Inhibitors and Jak Inhibitors in Atopic Dermatitis: A Systematic Review. Medicina (Kaunas), 60(8) . doi.org/10.3390/medicina60081376
Furue M (2020). Regulation of Skin Barrier Function via Competition between AHR Axis versus IL-13/IL-4‒JAK‒STAT6/STAT3 Axis: Pathogenic and Therapeutic Implications in Atopic Dermatitis. J Clin Med, 9(11) . doi.org/10.3390/jcm9113741
Le Floc’h A, Allinne J, Nagashima K, et al. (2020). Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Rα antibody, is required to broadly inhibit type 2 inflammation. Allergy, 75(5), 1188-1204 . doi.org/10.1111/all.14151
Torres T, Mendes-Bastos P, Cruz MJ, et al. (2025). Interleukin-4 and Atopic Dermatitis: Why Does it Matter? A Narrative Review. Dermatol Ther (Heidelb), 15(3), 579-597 . doi.org/10.1007/s13555-025-01352-y
Also Known As
- IL-4
- IL4
Biological Relationships
Biological Interactions
- Stimulates Collagen Evidence: IL-4 promotes profibrotic collagen synthesis in fibroblasts via STAT6/Smad pathways in dermal fibrosis contexts. Mamalis et al. 2019 Arch Dermatol Res doi:10.1007/s00403-019-01972-3
- Stimulates Matrix metalloproteinase Evidence: IL-4 (type 2 cytokine) activates NF-kB and AP-1 in fibroblasts driving MMP upregulation. Entity text; Laronha & Caldeira 2020 cells9051076.
- Stimulates Skin barrier dysfunction Evidence: IL-4 suppresses filaggrin expression via STAT6 and suppresses elongase enzymes for ceramide synthesis – primary driver of barrier dysfunction feedback loop. PMC9386840
- Stimulates Transepidermal water loss Evidence: IL-4 via STAT6 downregulates FLG, loricrin, ceramide synthesis and tight junction proteins, causing elevated TEWL. PMC11356372
- Interacts with Interleukin-13 Evidence: IL-4 and IL-13 signal through shared type II receptor IL-4Ra/IL-13Ra1 and are functionally interdependent in AD. PMC7700181
- Interacts with Interleukin-6 Evidence: IL-4 modulates IL-6 production; bidirectional cross-regulation documented in skin inflammatory responses. Bozek et al. 2022 Medicina doi:10.3390/medicina58030367
- Interacts with Tumour necrosis factor Evidence: IL-4 and TNF-α co-regulate keratinocyte gene expression; TNF counteracts some IL-4-mediated differentiation effects. Kanelleas et al. 2022 JCM doi:10.3390/jcm11195633
- Inhibits Ceramides Evidence: IL-4 inhibits serine palmitoyltransferase, reducing de novo ceramide synthesis in keratinocytes independently of FLG genotype. Sakai 2025 J Dermatol doi:10.1111/1346-8138.70098
- Inhibits Claudin-1 Evidence: IL-4 activates JAK-STAT6 signalling, directly downregulating CLDN1 transcription alongside filaggrin and loricrin in the same signalling event (PMC3049863; JID 2023 doi:10.1016/j.jid.2023.07.027; entity full_description).
- Inhibits Corneocyte
- Inhibits Filaggrin Evidence: IL-4 directly suppresses FLG gene expression in keratinocytes regardless of genotype, reducing filaggrin to approximately 25% of baseline.
- Inhibits Keratinocyte Evidence: IL-4 and IL-13… suppress keratinocyte differentiation; directly reduce FLG gene expression and disrupt tight junction protein expression
- Inhibits Loricrin Evidence: IL-4 suppresses loricrin alongside filaggrin; the acquired barrier defect from type 2 inflammation is broader than filaggrin alone.
- Associated disease Psoriasis Evidence: IL-4 modulates psoriatic immune balance; elevated in psoriasis patients vs healthy controls. Bozek et al. 2022 Medicina doi:10.3390/medicina58030367
- Associated disease Rosacea Evidence: Th2 skewing including IL-4 elevation documented in rosacea. Du et al. 2024 Front Immunol doi:10.3389/fimmu.2024.1367994
- Affects Cellular senescence Evidence: Th2 cytokine microenvironment driven by IL-4 accelerates fibroblast senescence in chronically inflamed skin. Mamalis et al. 2019 Arch Dermatol Res doi:10.1007/s00403-019-01972-3
- Affects Inflammageing Evidence: Chronic Th2 cytokine IL-4 drives low-grade skin inflammation overlapping with inflammageing phenotype. Duarte et al. 2025 Dermatol Ther doi:10.1007/s13555-025-01352-y
- Affects Skin ageing Evidence: IL-4-driven chronic barrier disruption and MMP upregulation contribute to accelerated dermal ageing. Mamalis et al. 2019 Arch Dermatol Res doi:10.1007/s00403-019-01972-3
Influenced By
- this Stimulated by Transepidermal water loss Evidence: Elevated TEWL activates TLR-mediated innate immune responses driving IL-4 production in AD. PMC12553588
- this Affected by Dermatitis Evidence: Atopic dermatitis driven by Th2/IL-4 immune polarisation that suppresses filaggrin; both IL-4 and IL-13 are produced in AD skin and perpetuate the barrier-immune cycle (PMC7432778).
Learn More
This topic is discussed in 2 articles:
-
Inflammatory cytokine that suppresses barrier protein production, perpetuating barrier dysfunction during inflammatory skin conditions.
-
Inflammatory cytokine that actively suppresses production of barrier proteins including filaggrin and claudin-1