Interleukin-1: Role in Immune Response and Therapeutic Targeting
Interleukin-1 (IL-1) is a potent proinflammatory cytokine that serves as a central mediator of innate immunity and inflammation, with IL-1 blockade representing a life-changing therapeutic strategy for autoinflammatory diseases and severe inflammatory conditions. 1
Physiological Role and Biological Properties
Core Inflammatory Functions
IL-1 drives inflammation through three primary mechanisms: inducing release of inflammatory mediators, activating inflammatory cells, and up-regulating adhesion molecules on endothelial cells. 2, 3
IL-1 exists as two main isoforms (IL-1α and IL-1β), both approximately 17 kD proteins that function as soluble mediators produced by macrophages, microglia, astrocytes, oligodendrocytes, neurons, and keratinocytes. 3, 4
IL-1 antigen concentration and activity increase dramatically during acute inflammatory responses, with 16-fold and 61-fold increases respectively documented during acute inflammation. 2
IL-1 specifically promotes macrophage chemotaxis through induction of macrophage inflammatory protein-1 (MIP-1), which recruits monocytes and macrophages to sites of inflammation. 2
Temporal Pattern in Inflammatory Cascades
IL-1 rises early within the first week of inflammatory responses and initiates the inflammatory cascade, preceding other cytokines like TNF-α (which peaks Days 14-28) and IL-6 (which peaks around week 2). 2
The combination of IL-1, IL-6, and TNF-α produces synergistic inflammatory effects more pronounced than any single cytokine alone, creating a self-amplifying cascade. 2
Cytokine Storm and Severe Inflammatory States
In severe infections like COVID-19, SARS, and MERS, IL-1 (along with IL-6 and TNF-α) drives cytokine release syndrome (CRS) and is significantly more elevated in patients with severe compared to uncomplicated disease. 1
IL-1β secretion occurs through NLRP3 inflammasome activation, particularly in SARS-CoV-2 infection within lymphoid cells, with increased serum IL-1β correlating with disease severity. 1
IL-1-driven macrophage activation occurs simultaneously with lymphocyte depletion through direct cytotoxic effects and apoptosis induction, creating an imbalanced immune response. 2
Therapeutic Targeting of IL-1
FDA-Approved IL-1 Blockade
IL-1 inhibition with agents like canakinumab (ILARIS) has been life-changing for patients with IL-1-mediated autoinflammatory diseases, significantly improving outcomes in conditions that previously had poor prognosis. 1, 5
Specific Disease Applications
For IL-1-mediated autoinflammatory diseases including CAPS (cryopyrin-associated periodic syndromes), TRAPS (TNF receptor-associated periodic syndrome), MKD (mevalonate kinase deficiency), and DIRA (deficiency of IL-1 receptor antagonist), IL-1 blockade is the primary therapeutic strategy. 1
These conditions range from mild (familial cold autoinflammatory syndrome) to severe (NOMID/CINCA) phenotypes, all caused by genetic mutations leading to dysregulated IL-1 production. 1
When untreated, patients with severe clinical phenotypes have poor prognosis with variable multiorgan involvement, making early IL-1 blockade critical. 1
Emerging Applications
Anti-IL-1 biologics show potential for COVID-19-related acute respiratory distress syndrome, based on evidence of NLRP3 inflammasome activation and elevated IL-1β in severe cases. 1
Tocilizumab (anti-IL-6) has demonstrated efficacy in cytokine storm, with 90% recovery in severe COVID-19 respiratory syndrome, suggesting that targeting the IL-1/IL-6/TNF-α axis may be beneficial. 1
Critical Safety Considerations
Infection Risk
IL-1 blockade increases risk of serious infections, including tuberculosis reactivation and opportunistic infections, requiring mandatory screening for active and latent TB before initiating therapy. 5
All patients must undergo appropriate tuberculosis screening tests prior to IL-1 inhibitor initiation, with treatment of latent TB according to CDC guidelines before starting therapy. 5
Patients should be instructed to seek immediate medical attention for signs of infection (persistent cough, weight loss, subfebrile temperature) during or after IL-1 blockade. 5
Drug Interactions and Contraindications
Concomitant use of IL-1 inhibitors with TNF blockers or other IL-1 blocking agents is not recommended due to increased risk of serious infections and neutropenia. 5
Live vaccines must be avoided during IL-1 blockade therapy, as IL-1 inhibition may interfere with normal immune response to new antigens. 5
Complete all recommended vaccinations (pneumococcal, inactivated influenza) prior to initiating IL-1 blockade when feasible. 5
For patients on CYP450 substrates with narrow therapeutic index (e.g., warfarin), therapeutic monitoring is required upon IL-1 blockade initiation, as normalization of CYP450 enzyme formation may alter drug metabolism. 5
Monitoring Requirements
Physicians must remain vigilant for macrophage activation syndrome (MAS), a life-threatening complication particularly in Still's disease patients, triggered by infection or disease worsening. 5
Hypersensitivity reactions including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported, requiring immediate discontinuation if severe reactions occur. 5
Regulatory Balance and Pathophysiology
Deficiency in anti-inflammatory cytokine IL-10, which normally regulates IL-1, TNF-α, and IL-8 production, predisposes to chronic inflammation with sustained macrophage activation and lymphocyte suppression. 2
IL-1 receptors are expressed in most cells, though often fewer than 100 receptors per cell, yet IL-1 remains active in the picomolar to femtomolar range. 6
Based on IL-1β knockout mice and short-term receptor blockade studies, IL-1β does not play a role in normal development or homeostasis (metabolism, hematopoiesis, renal/hepatic function, blood pressure regulation). 6
IL-1α is constitutively produced by epithelial cells, keratinocytes, and brain cells, potentially contributing to cell growth and repair functions distinct from IL-1β's inflammatory role. 6
Clinical Pitfalls to Avoid
Do not delay IL-1 blockade in confirmed autoinflammatory diseases while awaiting genetic confirmation, as clinical phenotype may warrant empiric treatment. 1
Avoid misinterpreting symptoms of underlying autoinflammatory disease as hypersensitivity reactions to IL-1 inhibitors, as these can be clinically similar. 5
Do not overlook endotoxin contamination (LPS) in research or clinical settings, as it can artificially induce IL-1β, IL-6, and TNF-α production, leading to misinterpretation of inflammatory patterns. 2
Recognize that IL-1 family includes multiple members (IL-18, IL-33, IL-36, IL-37, IL-38) with distinct roles in inflammation and immunity, requiring specific targeting strategies. 7, 8