Interleukins

1. Introduction

• Interleukins (ILs) are a subgroup of cytokines—small, secreted proteins—primarily involved in cell signaling within the immune system.

• Produced by leukocytes and various other cells in the body.

• Regulate immune cell differentiation, proliferation, activation, migration, and survival.

• Act via binding to specific cell surface receptors, triggering intracellular signaling pathways.

• In pharmacology, “Interleukins” may refer to recombinant forms used as immunotherapeutic agents or interleukin-targeting drugs (agonists or antagonists).

---

2. Classification and Numbering

• Named according to their order of discovery: IL-1 to IL-38 identified to date.

• Each interleukin has unique sources, target cells, and biological functions.

• Functionally grouped into:

  • Pro-inflammatory interleukins (e.g., IL-1, IL-6, IL-17).

  • Anti-inflammatory/regulatory interleukins (e.g., IL-10, IL-35).

  • Hematopoietic growth factors (e.g., IL-3, IL-7).

  • T-helper cell differentiation cytokines (e.g., IL-12, IL-4, IL-23).

---

3. Mechanism of Action

• Interleukins bind to their specific high-affinity receptors on target immune cells.

• Receptor engagement triggers JAK/STAT, MAPK, or NF-κB signaling pathways.

• The downstream effect depends on the interleukin type and the immune cell involved, leading to changes in gene expression and immune cell activity.

---

4. Therapeutic Interleukin Agents

A. Recombinant Interleukins (Agonists)

• Aldesleukin (recombinant IL-2) – used in metastatic renal cell carcinoma and metastatic melanoma; stimulates cytotoxic T lymphocytes and NK cells.

• Oprelvekin (recombinant IL-11) – used to prevent severe thrombocytopenia after chemotherapy by stimulating platelet production.

B. Interleukin Antagonists / Inhibitors

• Anakinra – IL-1 receptor antagonist for rheumatoid arthritis, cryopyrin-associated periodic syndromes.

• Canakinumab – monoclonal antibody targeting IL-1β for periodic fever syndromes and systemic juvenile idiopathic arthritis.

• Tocilizumab / Sarilumab – IL-6 receptor antagonists for rheumatoid arthritis, cytokine release syndrome.

• Secukinumab / Ixekizumab – IL-17A inhibitors for psoriasis, ankylosing spondylitis.

• Ustekinumab – targets IL-12/IL-23 p40 subunit for psoriasis, psoriatic arthritis, Crohn’s disease.

---

5. Indications for Therapeutic Interleukins

Agonists

• Cancer immunotherapy.

• Hematologic recovery post-chemotherapy.

Antagonists

• Autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus).

• Autoinflammatory syndromes.

• Psoriasis and psoriatic arthritis.

• Inflammatory bowel disease.

• Cytokine storm / cytokine release syndrome (e.g., CAR-T therapy complications).

---

6. Contraindications

• Known hypersensitivity to the drug or excipients.

• Active severe infection (for agonists and antagonists).

• For agonists: significant cardiac or pulmonary disease may be a relative contraindication.

---

7. Adverse Effects

A. Common

• Fatigue, flu-like symptoms (fever, chills, myalgia).

• Injection site reactions.

B. Serious

• Severe infection (due to immunosuppression with antagonists).

• Cytokine release syndrome (with agonists).

• Organ dysfunction (e.g., IL-2–associated capillary leak syndrome).

• Hematologic abnormalities (neutropenia, thrombocytopenia).

---

8. Drug Interactions

• Immunosuppressants – additive risk of infection when combined with interleukin antagonists.

• Live vaccines – avoid during and after immunosuppressive interleukin therapy due to diminished vaccine efficacy and risk of infection.

• CYP450 substrates – IL-6 inhibitors can alter CYP450 enzyme activity, affecting metabolism of drugs such as warfarin, cyclosporine, and statins.

---

9. Monitoring Requirements

• CBC with differential (baseline and periodically).

• Liver function tests.

• Renal function (especially for IL-2 therapy).

• Signs of infection during therapy.

• For IL-6 inhibitors: lipid profile.

---

10. Advantages and Limitations

Advantages

• Targeted immune modulation—either stimulation (agonists) or suppression (antagonists).

• Can address specific cytokine pathways in complex inflammatory diseases.

Limitations

• High cost and limited availability.

• Risk of severe infections or immune dysregulation.

• Some agents require IV infusion or frequent injections.