Elicit: Adalimumab and Inflammatory Pathways
Adalimumab inflammatory signaling pathways
Adalimumab modulates NF-κB, JAK/STAT, TNFα-TGFβ, Notch-1, IL-17, and IL-12/23 signaling pathways through direct TNF-α blockade, with pathway-specific effects varying by cell type, disease context, and treatment duration, mediated by coordinated changes in gene expression, protein levels, and microRNA regulation.
Abstract
Adalimumab modulates multiple interconnected inflammatory signaling pathways through direct TNF-α blockade and subsequent downstream effects. In keratinocytes, adalimumab primarily targets NF-κB signaling by downregulating IKBKB, IRAK1, TRAF2, MAP3K7, and TNFAIP3, with IKBKB functioning as a central hub in protein-protein interaction networks. In T cells, the dominant mechanism involves JAK/STAT pathway modulation, with adalimumab increasing STAT6 phosphorylation and restoring STAT4 activation to healthy levels, while disrupting Th1, Th17, and Th22 pathways in psoriasis patients....
Results
Characteristics of Included Studies
The included studies investigated adalimumab effects on inflammatory signaling pathways across diverse experimental contexts, ranging from in vitro cell culture systems to clinical trials in patients with inflammatory diseases.
Study
| Full text retrieved? | Experimental context | Cell type/tissue | Disease model | Inflammatory stimulus |
|---|---|---|---|---|
| Yes | Randomized controlled trial | Patient samples | Psoriasis (moderate-to-severe) | Adalimumab (blocks TNF-α) |
| No | Cell culture | Normal human dermal fibroblasts | Psoriasis | None mentioned |
| No | Cell culture | Normal human dermal fibroblasts | None (healthy cells) | Adalimumab (8 µg/ml) |
| Yes | Cell culture | Human keratinocytes (HaCaT) | Psoriasis | Lipopolysaccharide A (LPS) |
| Yes | Cell culture | Immortalized keratinocytes (HaCaT) | Psoriasis | Lipopolysaccharide (LPS) |
| Yes | Ex vivo cell culture | Fibroblast-like synoviocytes | Juvenile idiopathic arthritis | Adalimumab (TNFα inhibitor) |
| No | Cell culture | Normal human fibroblasts | General fibroblast response | Lipopolysaccharide (LPS) |
| No | Patient samples | CD4+ T cells (PBMCs) | Rheumatoid arthritis | Anti-CD3/anti-CD28, IL-4, IL-12 |
| No | Patient samples or ex vivo tissue | T cells | Inflammatory bowel disease | TNFα |
| No | Patient samples | Th1, Th17, Th22 cells (blood) | Psoriasis (moderate-to-severe) | None mentioned |
... (more results of pathway modulation detailed)
Inflammatory Pathways Modulated by Adalimumab
NF-κB Signaling Pathway
The NF-κB pathway emerged as a central target of adalimumab modulation in keratinocytes. Adalimumab reversed LPS-induced upregulation of multiple NF-κB-associated genes, including IKBKB, IRAK1, TRAF2, MAP3K7, and TNFAIP3. The NF-κB pathway also showed crosstalk with MAPK and JAK/STAT pathways and participates in the TNF-α/IL-23/IL-17 axis that is central to psoriatic inflammation.
JAK/STAT Signaling Pathway
JAK/STAT pathway modulation occurred across multiple experimental contexts. In normal human dermal fibroblasts, adalimumab affected 18 of 37 JAK/STAT-associated mRNAs...
TNFα-TGFβ Signaling Axis
In juvenile idiopathic arthritis synoviocytes, adalimumab demonstrated differential effects on persistent versus extended-to-be (ETB) fibroblast-like synoviocytes...
Notch-1 Signaling Pathway
In inflammatory bowel disease, adalimumab revealed a novel mechanism involving Notch-1 signaling...
Th1/Th17/Th22 Pathways
Clinical studies in psoriasis patients demonstrated that adalimumab disrupts multiple T helper cell pathways simultaneously...
Functional Consequences of Pathway Modulation
Adalimumab reduced key inflammatory markers across multiple studies. In psoriasis patients, treatment decreased serum CRP, IL-6, TNF, and GlycA at both 12 and 52 weeks. The reduction in these systemic inflammatory markers was statistically significant compared to placebo...
Conclusion
We demonstrate that FLS isolated from synovial fluid of patients with JIA are capable of secreting pro-inflammatory cytokines and promoters of inflammation. Specifically, in patients who ultimately extend to a polyarticular course, FLS overexpress cytokines associated with TNFα signaling.