Biopharmaceuticals and Cytokines Overview

Biopharmaceuticals

• Biopharmaceuticals are regulatory proteins secreted by hematopoietic and non-hematopoietic cells.
• They modulate innate and adaptive immune systems.
• They influence immune system development, cell growth, differentiation, and the inflammatory cascade.

Cytokines

• Coined in 1974 by Stanley Cohen.
• A group of regulatory proteins.
• Include interleukins (ILs), interferons (IFs), tumor necrosis factor alpha (TNF-α), growth factors (EGF, IGF), and transforming growth factors alpha, beta, and gamma (TGF-α,β,γ).

Cytokine Signaling Pathway 1

• Cytokines signal through binding to transmembrane receptors.
• Low-affinity ligand-binding domains ensure cytokine specificity.
• High-affinity effector domains activate target genes through intracellular signaling.

Cytokine Signaling Pathway 2

• Cytokines can act in several ways.
• Synergy: combined action produces a different result than individual actions.
• Antagonism: cytokines counteract each other's actions.
• Pleiotropy: one cytokine can affect multiple target cells.
• Redundancy: multiple cytokines can trigger similar responses.
• Pathway activation: a chain reaction or cascade of cytokine actions.

Interleukins

• A large group of cytokines with molecular weights (MWs) ranging from 15 to 30 kDa.
• 33 different members (IL-1 to IL-33).
• Mostly glycosylated, except for IL-1.
• Produced by various cell types (at least 17).
• Bind to specific receptors on target cells.
• Primarily exhibit paracrine activity, with some autocrine activity.

IL-1

• Known as Lymphocyte activating factor (LAF) with two distinct forms (IL-1α and IL-1β).
• Bind to the same receptor, inducing similar biological activity.
• Share 20% amino acid homology and arise from different genes on chromosome 2.
• Secreted as precursors, cleaved to mature polypeptides.
• Non-glycosylated.

IL-1 Biological Activities

• Pro-inflammatory cytokine that promotes the synthesis of enzymes (e.g., proteases) and generates inflammatory mediators.
• At high levels, it acts in an endocrine manner, inducing fever and general body wasting.
• Linked to some cancers.
• An IL-1 antagonist exists, binding to the IL-1 receptor without triggering intracellular responses.

Human IL-1 Receptor Antagonist

• A member of the IL-1 family.
• A competitive inhibitor of the IL-1 receptor.
• Competes with IL-1α and IL-1β for binding to the receptor.
• Prevents receptor dimerization and signaling.
• Suppresses pro-inflammatory cytokine responses.

IL-1α

• Secreted as a 271 amino acid precursor, cleaved to 159 amino acids.

IL-1β

• Secreted as a 229 amino acid precursor, cleaved to 153 amino acids.

IL-1 Secretion Mechanism

• Produced by various cells (e.g., endothelial cells, fibroblasts, monocytes, keratinocytes).
• Induces a wide array of biological activities.
• Activates B-lymphocytes.
• Plays a role in T-lymphocyte activation.

IL-2

• Also known as T-cell growth factor.
• The most studied interleukin.
• Plays a central role in the immune response.
• Produced by T cells in response to antigenic and mitogenic stimulation.
• Required for T-cell proliferation and various immune responses.
• Binds to B-cells, monocytes, lymphokine-activated killer cells, natural killer cells, and glioma cells.

IL-2 Structure

• Single-chain polypeptide (133 amino acids).
• Glycoprotein, with a carbohydrate component attached to a threonine residue.
• Molecular mass of 15-20 kDa, depending on glycosylation.
• Carbohydrate chain is not required for biological activity.

IL-2 Receptor

• Alpha and beta subunits have low affinity for IL-2.
• Alpha, beta, andgamma trimer complex binds IL-2 with high affinity.
• Associated with various immune cells, promoting growth and differentiation.
• Functions as a central molecular switch, activating immune responses.

Proleukin (Aldesleukin)

• Recombinant IL-2 produced in E. coli.
• Non-glycosylated but functional.
• Lacks N-terminal alanine and has a C125S substitution.
• Used in treating metastatic melanoma and renal cell carcinoma.

Neumega (Oprelvekin)

• Recombinant IL-11 produced in E. coli.
• Non-glycosylated, 19 kDa, 177 amino acids, lacking N-terminal proline.
• A comparable activity to natural IL-11.
• Primarily used to prevent or reduce severe thrombocytopenia after myelosuppressive chemotherapy.

IL-11

• Additional cytokine with general medical use approval.
• Produced mostly by IL-1-activated bone marrow cells.
• Functions as a hematopoietic growth factor.
• Stimulates platelet production and bone marrow cell growth and differentiation.
• 23 kDa polypeptide (178 amino acids).
• Binds to a transmembrane receptor.

This quiz covers essential concepts about biopharmaceuticals, including their role in regulating immune systems, and highlights the key aspects of cytokines and their signaling pathways. It explores the functions of various cytokines and the mechanisms of their action, providing a foundational understanding of their biological significance.