Cytokine signaling
JAK/STAT (STAT3)
Also searched as JAK/STAT (STAT3).
Essential for defense, harmful when it runs hot — you want a responsive relay, not a stuck one.
In depth
A cytokine signaling relay. The evidence shows a finding that inverts the intuitive reading: blocking jak in macrophages increased inflammatory output, because it removed an IL-10 feedback brake. 'Calming' this pathway is not straightforwardly calming.
What drives it
Innate immune sensor increases it.
10.1186/s10020-024-00845-4 — TLR4/type-I-IFN study 2003, Nat Immunol — TLR4/LPS induces IFN-β, which acts through the JAK-family kinase Tyk2 and STAT signaling; Tyk2/IFN-β are essential effectors of LPS responses. doi 10.1186/s10020-024-00845-4
Interferon response increases it.
Note: a JAK-STAT-independent route also exists -- IFN-beta can bind IFNAR1 without IFNAR2 and activate a distinct gene response. Provenance: previously cited PMC7255347 could not be confirmed and has been replaced. PMC7255347
What it drives
It increases Inflammatory signaling.
Th17/STAT3 review 2010 — IL-6/IL-21 activate STAT3 (a JAK-STAT effector), which induces RORγt and drives Th17 differentiation and IL-17 production. PMID 20499411 Verbatim: “IL-6, signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappaB (NF-kB) pathways were implicated in the TLR2 stimulated IL-17 and IL-23”. doi 10.1186/ar3780 · PMID 20499411 · PMC3446432
It increases Immune support.
PMC11565648 — Darnell, Kerr & Stark 1994, Science 264:1415 — JAK-STAT signaling transduces cytokine and interferon signals into transcriptional activation of immune-response genes. PMC11565648
It increases Calm skin barrier.
Verified at source (Pharmacol Res 2025, doi 10.1016/j.phrs.2025.107968 / S0753332225007024): in AD, increased allergen penetration and Th2 cytokine signaling — notably IL-4 and IL-13 — drive jak/stat-mediated repression of skin-barrier genes including filaggrin (flg), loricrin (lor), involucrin (ivl), claudin-1 (CLDN1) and aquaporin-3 (AQP3), producing impaired keratinocyte differentiation, tight-junction disruption and increased skin permeability. This names the route by which the cytokine reaches the tissue, which the direct IL-13 arrow leaves implicit. The finding that matters most here, and it cuts both ways: blocking one axis can convert the disease into the other. Targeting the TNF/IL-17/23 axis in psoriasis, or the IL-4/13 axis in atopic dermatitis, can produce a phenotypic shift toward the opposite disease. In dupilumab-treated AD patients (IL-4/IL-13 blockade), plasma IL-17A and TNF-alpha were significantly elevated versus healthy controls and tslp remained persistently high — consistent with reported psoriasiform eruptions on dupilumab, understood as a shift toward Th1/Th17 dominance once Th2 is suppressed (PMC12968250). Suppressing a dominant pathway can unmask alternative immune axes. Psoriasis and AD also share a final common pathway of barrier-gene repression and barrier fragility despite opposite immune profiles. doi 10.1016/j.phrs.2025.107968 · PMC12968250
Blends that modulate it
Each blend page names this pathway and carries the study behind its claim.
See it on the map
Open the causal map to follow this pathway upstream and downstream, arrow by arrow, each with its study.