What are the differences in functioning, structure, and origin between Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF), and can they be considered neuropeptides?

Differences Between IL-1 and TNF: Structure, Function, and Origin

Structural Differences

IL-1 and TNF are structurally distinct proinflammatory cytokines that belong to different protein families and have fundamentally different molecular architectures. 1

• TNF-α exists in two biologically active forms: a transmembrane precursor (tmTNF) and a soluble cytokine (sTNF) released after cleavage from the cell surface 1
• IL-1 exists primarily as two isoforms (IL-1α and IL-1β), both approximately 17 kD proteins that function as soluble mediators 1, 2
• TNF-α binds to two distinct receptors: TNF receptor 1 (TNFR1, p55) and TNF receptor 2 (TNFR2, p75), leading to NF-κB activation and/or cell apoptosis 1
• IL-1 binds to its specific IL-1 receptor, which can be blocked by interleukin-1 receptor antagonist (IL-1Ra) at high concentrations 3

Cellular Origin and Production

Both cytokines are primarily produced by monocyte-macrophages, but their cellular sources extend to multiple cell types with some overlap. 2

• TNF-α is produced by macrophages, microglia, astrocytes, neurons, endothelial cells, and keratinocytes 1
• IL-1 (both α and β) is produced by microglia, astrocytes, oligodendrocytes, neurons, and keratinocytes 1
• Both cytokines can be produced by the same cell types in response to inflammatory stimuli, though their production kinetics differ 3

Functional Differences

Inflammatory Response Profiles

IL-1 and TNF exhibit distinct temporal and mechanistic profiles in mediating inflammation, despite producing similar biological effects. 4

• IL-1 induces PMN leukocyte accumulation that is slow in onset (peak at 3-4 hours), requires protein synthesis (inhibitable by Actinomycin D and Cycloheximide), and is not associated with significant plasma leakage 4
• TNF-α induces rapid PMN leukocyte accumulation and edema formation (half-life 6-10 minutes), is PMN leukocyte-dependent but not protein biosynthesis-dependent, and causes significant plasma leakage 4
• IL-1 plays a central role in inflammation by inducing release of inflammatory mediators, activating inflammatory cells, and up-regulating adhesion molecules on endothelial cells 1
• TNF-α promotes leukocyte extravasation, induces fever, and promotes vasodilation 1

Shared Pathophysiological Effects

Both cytokines work synergistically to drive tissue destruction and fibrosis in chronic inflammatory diseases. 1, 2

• IL-1 and TNF-α together induce high levels of matrix metalloproteinases (MMP) in fibroblasts, synovial cells, and chondrocytes 2
• Both cytokines induce fibroblast collagen production and cause pulmonary fibrosis in animal models 1
• TNF-α and IL-1 are the principal mediators of tissue destruction in immuno-inflammatory diseases such as rheumatoid arthritis 2

Kinetic Behavior During Infection

The temporal dynamics of IL-1 and TNF differ significantly during severe infections, with important clinical implications. 3

• During fulminant septicemia, TNF plasma concentration increases only transiently during the very early stage of infection 3
• IL-1 antigen concentration and activity increase 16-fold and 61-fold respectively during the first week, with TNF-α rising later (highest levels Days 14-28) 1
• Peripheral blood cells cannot be stimulated to produce IL-1β during acute severe infectious diseases, while IL-1Ra production remains unaffected 3

Signal Transduction Mechanisms

Despite activating similar transcription factors and producing comparable biological effects, IL-1 and TNF utilize distinct receptor-proximal signaling pathways that converge on common downstream cascades. 5

• Both cytokines activate the same set of transcription factors through members of the MAPKK kinase protein family 5
• TNF receptor associated factors (TRAFs) serve as the link between receptor-proximal events and common MAPKK kinases 5
• Different pathway-specific TRAFs are used by TNF-α and IL-1 to activate the same MAPKK kinase-controlled cascades 5

Regulatory Control

Natural inhibitors differentially regulate IL-1 and TNF activity through distinct mechanisms. 3

• Soluble TNF receptors (sTNFR1 and sTNFR2) are shed upon inflammatory stimuli and complex circulating TNF, preventing binding to effector cells 1, 3
• IL-1 receptor antagonist (IL-1Ra) blocks IL-1β binding to its receptor at high concentrations 3
• Anti-inflammatory cytokines IL-4 and IL-10 suppress gene expression and synthesis of both IL-1 and TNF 6, 2
• IL-10 considerably decreases production of IL-1, TNF-α, and metalloproteases while stimulating TIMP production 2

Are They Neuropeptides?

IL-1 and TNF are definitively NOT neuropeptides—they are cytokines with fundamentally different biochemical properties and functions. 1

Critical Distinctions

• Neuropeptides are small signaling molecules (typically 3-40 amino acids) produced by neurons and released from nerve terminals, such as substance P, neurokinins, and BDNF 1
• Cytokines like IL-1 and TNF are larger proteins (approximately 17 kD for IL-1, similar for TNF) produced primarily by immune cells, though they can be produced by neurons 1, 2
• While both IL-1 and TNF have receptors on neurons and can affect neuronal function, this does not make them neuropeptides 1
• The bioactivity of true neuropeptides is terminated by specific peptidases (NEP and DPP-IV), whereas cytokines are regulated by soluble receptors and receptor antagonists 1, 3

Neuroimmune Communication

• IL-1 and TNF function as neuroimmune communicators rather than neuropeptides, mediating bidirectional communication between the immune and nervous systems 1
• Both cytokines can affect the central nervous system to initiate fever and other systemic responses 7
• Tumor-derived IL-1, IL-6, and TNF-α can affect neuroendocrine control of appetite, leading to anorexia 1
• These cytokines represent inflammatory mediators that influence neurological function, distinct from the classical definition of neuropeptides produced by and acting primarily within the nervous system 1