What are the protein cytokines involved in ulcerative colitis?

Protein Cytokines in Ulcerative Colitis

Ulcerative colitis is characterized by elevated levels of multiple pro-inflammatory cytokines, with IL-1β, TNF-α, IL-6, and IL-8 being the most prominently elevated and clinically relevant protein cytokines in the inflamed colonic mucosa. 1

Primary Pro-Inflammatory Cytokines

The core inflammatory cytokine network in UC consists of four major players that are consistently elevated in active disease:

• IL-1β (Interleukin-1 beta) shows the strongest correlation with disease activity among all measured cytokines and is produced in large amounts in UC patients 1
• TNF-α (Tumor Necrosis Factor-alpha) is highly elevated and shows significant correlation with IL-1β and IL-8 levels 1
• IL-6 (Interleukin-6) is markedly increased in inflamed mucosa and correlates with systemic inflammation markers, particularly circulating platelet counts 1
• IL-8 (Interleukin-8) demonstrates strong correlation with both TNF-α and IL-1β in a coordinated inflammatory response 1

These four cytokines work in a highly interconnected network, with multivariate analysis demonstrating that IL-1β provides the best correlation with clinical disease activity 1

Additional Pro-Inflammatory Cytokines

Beyond the core four cytokines, UC involves several other inflammatory mediators:

• IL-17A is elevated in inflamed colonic tissue as part of Th17-mediated inflammation 2, 3
• IL-33 shows increased expression in active UC 3
• IFN-γ (Interferon-gamma) is present, though UC is not primarily a Th1-driven disease like Crohn's disease 3, 4
• IL-13 is particularly important in UC pathogenesis, arising from a Th2-like differentiation process and natural killer T cells 4

Chemokines and Inflammatory Mediators

Several chemokines are significantly elevated in UC:

• IP-10 (Induced Protein-10) is increased in inflamed versus uninflamed areas 2
• MCP-1 (Monocyte Chemoattractant Protein-1) shows elevation in active inflammation 2
• MIP-1α and MIP-1β (Macrophage Inflammatory Proteins) are both elevated in inflamed colonic mucosa 2

Anti-Inflammatory and Regulatory Cytokines

The inflammatory response in UC also involves regulatory cytokines, though their levels may not adequately counterbalance the pro-inflammatory state:

• IL-10 (Interleukin-10) is present but may be insufficient to control inflammation 3, 5
• IL-35 has been measured in UC tissue 3
• TGF-β (Transforming Growth Factor-beta) is expressed in the colonic mucosa 3

Soluble Receptors and Regulatory Proteins

• IL-1Ra (Interleukin-1 Receptor Antagonist) is increased in inflamed areas and shows particular elevation in patients with severe histological scores (Geboes score ≥4) 2
• IL-2Rsp (Soluble IL-2 Receptor) levels are significantly different between UC patients and healthy controls 5

Clinical Implications and Therapeutic Targets

The therapeutic landscape reflects this cytokine complexity, with current AGA guidelines recommending TNF-α antagonists (infliximab, adalimumab, golimumab), IL-12/IL-23 inhibitors targeting the p40 subunit (ustekinumab), and IL-23 inhibitors (risankizumab, guselkumab, mirikizumab) for moderate-to-severe UC 6, 7

Important Caveats:

• Both inflamed and adjacent "uninflamed" mucosal areas share similar inflammatory molecular pathways, though they can be differentiated endoscopically and histologically based on specific cytokine levels 2
• The cytokine profile in UC differs from Crohn's disease, with UC showing higher levels of inflammatory cytokines overall and a different T-cell differentiation pattern (Th2-like in UC versus Th1/Th17 in Crohn's) 1, 4
• The complexity of this multi-cytokine network highlights the major limitation of single-target therapeutic strategies, as blocking one cytokine may not adequately address the redundant inflammatory pathways 2