Abstract

There is an expanding role for interleukin (IL)-1 in diseases from gout to cancer. More than any other cytokine family, the IL-1 family is closely linked to innate inflammatory and immune responses. This linkage is because the cytoplasmic segment of all members of the IL-1 family of receptors contains a domain, which is highly homologous to the cytoplasmic domains of all toll-like receptors (TLRs). This domain, termed "toll IL-1 receptor (TIR) domain," signals as does the IL-1 receptors; therefore, inflammation due to the TLR and the IL-1 families is nearly the same. Fundamental responses such as the induction of cyclo-oxygenase type 2, increased surface expression of cellular adhesion molecules and increased gene expression of a broad number of inflammatory molecules characterizes IL-1 signal transduction as it does for TLR agonists. IL-1β is the most studied member of the IL-1 family because of its role in mediating autoinflammatory disease. However, a role for IL-1α in disease is being validated because of the availability of a neutralizing monoclonal antibody to human IL-1α. There are presently three approved therapies for blocking IL-1 activity. Anakinra is a recombinant form of the naturally occurring IL-1 receptor antagonist, which binds to the IL-1 receptor and prevents the binding of IL-1β as well as IL-1α. Rilonacept is a soluble decoy receptor that neutralizes primarily IL-1β but also IL-1α. Canakinumab is a human monoclonal antibody that neutralizes only IL-1β. Thus, a causal or significant contributing role can be established for IL-1β and IL-1α in human disease.

Highlights

  • There is an expanding role for interleukin (IL)-1 in diseases from gout to cancer

  • IL-1: More than the “Fever Molecule” During the late 1970s, what is called IL-1 had been studied under different names such as leukocytic pyrogen, leukocyte endogenous mediator, mononuclear cell factor, catabolin and others

  • As autoimmune diseases respond to therapies such as TNFα neutralization, CTLA4-Ig, anti–IL-6 receptor, depletion of CD20 B cells and anti–IL-12/IL-23 and IL-17 neutralizing antibodies, these agents show no benefit in patients with autoinflammatory diseases

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Summary

Introduction

There is an expanding role for interleukin (IL)-1 in diseases from gout to cancer. More than any other cytokine family, the IL-1 family is closely linked to innate inflammatory and immune responses. As autoimmune diseases respond to therapies such as TNFα neutralization, CTLA4-Ig, anti–IL-6 receptor, depletion of CD20 B cells and anti–IL-12/IL-23 and IL-17 neutralizing antibodies, these agents show no benefit in patients with autoinflammatory diseases. Steady-state mRNA levels of IL-1β, caspase-1, IL-1α, IL-6 and TNFα are elevated in blood monocytes from patients with neonatal-onset multisystem inflammatory disease (NOMID) compared with cells from healthy subjects but decrease with treatment with anakinra [23].

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Conclusion

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