Interrelationship and Sequencing of Interleukins4, 13, 31, and 33 – An Integrated Systematic Review: Dermatological and Multidisciplinary Perspectives

Figures & data

Table 1 IL-4, IL-13, IL-31 and IL-33-Secreting Cells, with the Respective IL Receptors and Signaling Pathways Which They Activate

Cytokine	Secreting Cells	Receptors	Activated Signaling Pathway
IL-4	Th2 cells, mast cells, eosinophils, basophils	IL-4 receptor alpha chain (IL-4Rα)	JAK/STAT and IRS-1/IRS-2 pathways
IL-13	Th2 cells, mast cells, eosinophils, basophils, NK cells, CD4+ T cells, nuocytes,	IL-4 receptor alpha chain (IL-4Rα), IL-13 receptor alpha 1 (IL-13Rα1),	JAK/STAT and IRS-1/IRS-2 pathways type II IL-4 receptor/ IL-13 receptor, which is comprised of IL-4Rα and IL-13Rα1.
IL-31	Th2 Ly, CD4+ T cells	IL-31RA, OSMR	PI3K/AKT, MAPK, STAT pathway, JAK1 and JAK2
IL-33	Macrophages, dendritic cells, damaged epithelial cells,	Interleukin 1 receptor-like 1 (ST2), ST2 is the only receptor for IL-33	IARK-1, IARK-4, and MAPK kinases, JNK, ERK1/ 2

Note: ^4–11.

Abbreviations: IL-, interleukin; Th, T helper lymphocytes; CD, cluster of differentiation; OSMR, oncostatin M receptor; JAK/STAT, Janus kinase-signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase; JNK, Jun kinase; ERK, extracellular signal-regulated kinase.

Figure 1 A snippet of the interleukin cascade. IL-4 and IL-13 are released under certain inflammatory stimuli. In turn they induce the release of IL-31, and IL-33; the latter is also induced by IL-31.

Figure 2 Compiling of results.

Notes: PRISMA figure adapted from Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. Creative Commons.¹⁹¹ For more information, visit: http://www.prisma-statement.org/.

Table 2 Overview of the Activities of IL-4, IL-13, IL-31 and IL-33

Interleukins	Activities
	Anti-Inflammatory	Pro-Inflammatory	Growth Factor Release	Pro-Fibrotic	Up-Regulating	Down-Regulating
IL-4	√	√	PDGF	√	p53, p21, JAK/STAT6, bax, caspase-3, −8, 9
IL-13	√			√	Amphiregulin
IL-31	√	√	EGF, VEGF	√	Matrix metalloproteinases 1, 3, 7, 25, IL-6, IL-16, IL-32
IL-33	√	√				bcl-2, iNOS

Note: ^{12,13,23,31,38–43,48,50–53,83,84,87,89,170}.

Abbreviations: IL-, interleukin; JAK/STAT, Janus kinase-signal transducer and activator of transcription; EGF, epidermal growth factor; VEGF, vascular endothelial growth factor; iNOS, the inducible nitric oxide synthase.

Table 3 Summary of Key Findings for IL-4, IL-13, IL-31, and IL-33

IL-4	IL-13	IL-31	IL-33
Promotes fibrosis Plays a role in fibrotic cardiac myopathy Plays a role in hypertensive cardiomyopathy Promotes atherosclerosis Promotes pulmonary hypertension Beneficial role in cardiac remodeling post-infarct Attenuates manifestations in AS Possible role in aggravating lupus nephritis Attenuates inflammation in RA Anti-tumor effects in melanoma Promotes pruritus- Promotes atopic dermatitis Key cytokine in systemic sclerosis Protective role in neuroinflammation Promotes cognition May play a role in Parkinson’s disease Neuroprotective role in infections Increases production of microglia	Promotes fibrosis Promotes cardiac remodeling Inhibits atherosclerosis May be a possible prognostic marker in myocardial infarction Promotes pulmonary hypertension Regulates inflammation in myocarditis Contributes to inflammation in SLE Possible diagnostic indicator in RA Diverse pro-tumor effects Promotes atopic dermatitis Key cytokine in systemic sclerosis Promotes cognition May play a role in Parkinson’s disease Protective role in neuroinfections Increases production of microglia	Promotes dilated cardiomyopathy (rs4758680 allele) Role in cardiac hypertrophy Key role in Kawasaki disease Upregulates matrix metalloproteinases Stimulates fibroblasts in SSc Promotes angiogenesis Promotes pruritus Promotes atopic dermatitis	Alarm factor as a response to stress Cardioprotective role Beneficial role in pressure-overload cardiac remodeling Inhibits atherosclerosis Beneficial role in cardiac remodeling post-infarct Inhibitory role in atopic dermatitis Possible marker in SSc Aggravates inflammation in RA; may predict response to certain treatments Promotes cognition Promotes motor neuron integrity in ALS Promotes neuroinflammation Modulates CNS myelination Reduces CNS Ischaemic damage Role in seizure recovery Promotes neuropathic pain Role in normal neural development

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