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. Adalimumab also affects the TNFα-TGFβ signaling axis differentially depending on disease context, effectively decreasing downstream inflammation in extended-to-be juvenile idiopathic arthritis synoviocytes but showing paradoxical increases in persistent disease. A novel mechanism was identified in inflammatory bowel disease involving Notch-1, which binds directly to TNFα and mediates adalimumab’s effects on T cell cycling but not apoptosis. MicroRNAs including miR-1297, miR-30a, miR-95-5p, miR-125b, and miR-4329 emerged as important regulators that fine-tune pathway responses, with temporal dynamics showing initial broad transcriptional changes followed by progressive miRNA restriction.

Methods

We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 7 key aspects that mattered most to the research question.

Records from Elicit search

n = 200

Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of Semantic Scholar and OpenAlex.

We ran this query: “Adalimumab inflammatory signaling pathways”

The search returned 200 total results from Elicit.

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. STRING analysis identified IKBKB as a central hub in the protein-protein interaction network, coordinating immune and apoptotic signals. This downregulation occurred consistently across multiple timepoints (2, 8, and 24 hours), with early suppression of certain genes and broader inhibition at later timepoints.

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, with time-dependent changes in regulatory microRNAs (20 miRNAs at 2 hours, 9 at 8 hours, and 3 at 24 hours). Specific pathway components showed distinct responses.

TNFα-TGFβ Signaling Axis

In juvenile idiopathic arthritis synoviocytes, adalimumab demonstrated differential effects on persistent versus extended-to-be (ETB) fibroblast-like synoviocytes. This suggests that adalimumab effectively decreases inflammation downstream of initial TNFα signaling in ETB cells.

Notch-1 Signaling Pathway

In inflammatory bowel disease, adalimumab revealed a novel mechanism involving Notch-1 signaling. Notch-1 mucosal expression increased in response to anti-TNFα treatment.

Th1/Th17/Th22 Pathways

Clinical studies in psoriasis patients demonstrated that adalimumab disrupts multiple T helper cell pathways simultaneously. After 12 weeks of adalimumab therapy, significant declines occurred in cell frequencies, transcription factor expression, and cytokine levels, indicating broad immunomodulation across these pathways.

Molecular Mechanisms of Pathway Modulation

Direct and Indirect Effects

Adalimumab’s primary direct mechanism involves blocking TNF-α through antibody binding, preventing TNF-α from interacting with its receptors. This direct inhibition triggers cascading indirect effects on downstream pathways.

Gene Expression and Protein Level Changes

Adalimumab induced coordinated changes at transcriptional and translational levels. In keratinocytes, adalimumab downregulated NF-κB-associated genes with concordant protein-level reductions.

MicroRNA Involvement

MicroRNAs emerged as important mediators of adalimumab’s effects. In NF-κB pathway modulation, anti-inflammatory miRNAs showed reciprocal expression changes consistent with anti-inflammatory activity.

Functional Consequences of Pathway Modulation

Inflammatory Mediator Production

Adalimumab reduced key inflammatory markers across multiple studies. In psoriasis patients, treatment decreased serum CRP, IL-6, TNF, and glycoprotein acetylation (GlycA) at both 12 and 52 weeks.

Effects on Cell Function

Adalimumab influenced T cell function through multiple mechanisms. In rheumatoid arthritis, IFN-γ production increased in adalimumab-treated patients compared to untreated individuals.

Clinical and Phenotypic Improvements

Clinical improvements correlated with pathway modulation. In psoriasis, adalimumab improved skin disease and systemic inflammation markers.

Biomarker Changes

Several biomarkers emerged as indicators of pathway activity. Modulation of IL-6 levels served as a marker of response to TNF-α inhibitor treatment.

Adverse Effects

Adalimumab demonstrated potential adverse effects on lipid metabolism. At 52 weeks, cholesterol efflux and high-density lipoprotein particle count (HDL-p) were reduced.

References

[B. Grabarek, D. Wcisło-Dziadecka, K. Bednarek, C. Kruszniewska-Rajs, J. Gola
(2019).Assessment of transcriptional activity genes associated with the IL‐17 signaling pathway in skin fibroblasts under the influence of adalimumab. Dermatologic Therapy](/content/review/5a0c167a-c7da-401c-b709-0e88155712e5/source/ss-204330835/index.html)

[B. Grabarek, D. Wcisło-Dziadecka, J. Gola, C. Kruszniewska-Rajs, L. Brzezińska-Wcisło, and 2 more
(2018).Changes in the Expression Profile of JAK/STAT Signaling Pathway Genes and Mirnas Regulating their Expression Under the Adalimumab Therapy. Current Pharmaceutical Biotechnology](/content/review/5a0c167a-c7da-401c-b709-0e88155712e5/source/ss-51866220/index.html)

[Paulina Buda, P. Michalski, Oliwia Warmusz, A. MICHALSKA-BAŃKOWSKA, T. Sirek, and 5 more
(2023).Influence of adalimumab on interleukin 12/23 signalling pathways in human keratinocytes treated with lipopolysaccharide A. Advances in Dermatology and Allergology](/content/review/5a0c167a-c7da-401c-b709-0e88155712e5/source/ss-259569837/index.html)

[Aleksandra Plata-Babula, Wojciech Kulej, Paweł Ordon, Julia Gajdeczka, Martyna Stefaniak, and 4 more
(2025).Modulation of Nuclear Factor Kappa B Signaling and microRNA Profiles by Adalimumab in LPS-Stimulated Keratinocytes. International Journal of Molecular Sciences](/content/review/5a0c167a-c7da-401c-b709-0e88155712e5/source/ss-282162793/index.html)

[Megan M. Simonds, Samuel T. Freer, L. Al-Jaberi, A. Brescia
(2023).Adalimumab Effectively Decreases Inflammation Downstream of TNFα Signaling in Synoviocytes from Extended Oligoarticular Juvenile Idiopathic Arthritis. Rheumatology and Therapy](/content/review/5a0c167a-c7da-401c-b709-0e88155712e5/source/ss-266158906/index.html)

[Iwona Adwent, M. Schweizer, B. Grabarek, D. Boroń
(2020).Effect of adalimumab on the expression profile of mRNA, and protein associated with JAK/STAT signaling pathway in fibroblast exposed to lipopolysaccharide. Dermatologic Therapy](/content/review/5a0c167a-c7da-401c-b709-0e88155712e5/source/ss-215733847/index.html)

[N. Aerts, D. Ebo, C. Bridts, Mlt, W. Stevens, and 1 more
(2010).T cell signal transducer and activator of transcription (STAT) 4 and 6 are affected by adalimumab therapy in rheumatoid arthritis. Clinical and Experimental Rheumatology](/content/review/5a0c167a-c7da-401c-b709-0e88155712e5/source/ss-23284508/index.html)

[L. Werner, U. Berndt, D. Paclik, S. Danese, A. Schirbel, and 1 more
(2011).TNFα inhibitors restrict T cell activation and cycling via Notch-1 signalling in inflammatory bowel disease. Gut](/content/review/5a0c167a-c7da-401c-b709-0e88155712e5/source/ss-22951422/index.html)

[Li Luan, Shixin Han, Hua Wang, Xiaoming Liu
(2015).Down-regulation of the Th1, Th17, and Th22 pathways due to anti-TNF-α treatment in psoriasis. International Immunopharmacology](/content/review/5a0c167a-c7da-401c-b709-0e88155712e5/source/ss-24659693/index.html)

[N. Mehta, D. Shin, A. Joshi, A. Dey, A. Armstrong, and 20 more
(2018).Effect of 2 Psoriasis Treatments on Vascular Inflammation and Novel Inflammatory Cardiovascular Biomarkers: A Randomized Placebo-Controlled Trial. Circulation Cardiovascular Imaging](/content/review/5a0c167a-c7da-401c-b709-0e88155712e5/source/ss-21709511/index.html)