RESUMEN
The IL-10 family of cytokines is comprised of IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, and IFN-lambdas (IL-28A, IL-28B, and IL-29). The IL-10 family members bind to shared class II cytokine receptor chains that associate in various combinations in heterodimeric complexes. Upon interleukin/receptor complex formation, these proteins switch on the Jak/STAT pathway and elicit pleiotropic biological responses whose variety sharply contrasts with their structural similarities. IL-10 family members are involved in several human diseases and health conditions and hence their structural analyses may provide valuable information to design specific therapeutic strategies. In this review, we describe the human interleukin-10 family of cytokines, focusing on their structures and functions, with particular attention given to IL-22 and IL-10. We report on the recently published structures of IL-10 cytokine family members and their complexes with cognate transmembrane and soluble receptors as well as on interleukin physiology and physiopathology.
Asunto(s)
Interleucina-10/química , Interleucina-10/metabolismo , Interleucinas/química , Interleucinas/metabolismo , Modelos Moleculares , Receptores de Citocinas/metabolismo , Transducción de Señal/fisiología , Secuencia de Aminoácidos , Humanos , Interleucina-10/clasificación , Datos de Secuencia Molecular , Filogenia , Multimerización de Proteína , Alineación de Secuencia , Interleucina-22RESUMEN
Interleukin-22 (IL-22) plays an important role in the regulation of immune and inflammatory responses in mammals. The IL-22 binding protein (IL-22BP), a soluble receptor that specifically binds IL-22, prevents the IL-22/interleukin-22 receptor 1 (IL-22R1)/interleukin-10 receptor 2 (IL-10R2) complex assembly and blocks IL-22 biological activity. Here we present the crystal structure of the IL-22/IL-22BP complex at 2.75 A resolution. The structure reveals IL-22BP residues critical for IL-22 binding, which were confirmed by site-directed mutagenesis and functional studies. Comparison of IL-22/IL-22BP and IL-22/IL-22R1 crystal structures shows that both receptors display an overlapping IL-22 binding surface, which is consistent with the inhibitory role played by IL-22 binding protein.
Asunto(s)
Interleucinas/química , Receptores de Interleucina/química , Sitios de Unión/fisiología , Humanos , Inflamación/genética , Inflamación/metabolismo , Subunidad beta del Receptor de Interleucina-10/química , Subunidad beta del Receptor de Interleucina-10/genética , Subunidad beta del Receptor de Interleucina-10/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Mutagénesis Sitio-Dirigida , Unión Proteica/fisiología , Estructura Cuaternaria de Proteína/fisiología , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Interleucina-22RESUMEN
Interleukin-22 (IL-22) is a pleiotropic cytokine that is involved in inflammatory responses. Human IL-22 was incubated with its soluble decoy receptor IL-22BP (IL-22 binding protein) and the IL-22-IL-22BP complex was crystallized in hanging drops using the vapour-diffusion method. Suitable crystals were obtained from polyethylene glycol solutions and diffraction data were collected to 2.75 A resolution. The crystal belonged to the tetragonal space group P4(1), with unit-cell parameters a = b = 67.9, c = 172.5 A, and contained two IL-22-IL-22BP complexes per asymmetric unit.
Asunto(s)
Interleucinas/química , Interleucinas/metabolismo , Receptores de Interleucina/química , Receptores de Interleucina/metabolismo , Difracción de Rayos X , Cristalización , Humanos , Modelos Moleculares , Unión Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Solubilidad , Difracción de Rayos X/métodos , Interleucina-22RESUMEN
Interleukin-22 (IL-22) is a member of the interleukin-10 cytokine family, which is involved in anti-microbial defenses, tissue damage protection and repair, and acute phase responses. Its signaling mechanism involves the sequential binding of IL-22 to interleukin-22 receptor 1 (IL-22R1), and of this dimer to interleukin-10 receptor 2 (IL-10R2) extracellular domain. We report a 1.9A crystal structure of the IL-22/IL-22R1 complex, revealing crucial interacting residues at the IL-22/IL-22R1 interface. Functional importance of key residues was confirmed by site-directed mutagenesis and functional studies. Based on the X-ray structure of the binary complex, we discuss a molecular basis of the IL-22/IL-22R1 recognition by IL-10R2.
Asunto(s)
Interleucinas/química , Receptores de Interleucina/química , Secuencia de Aminoácidos , Línea Celular , Cristalografía por Rayos X , Humanos , Interleucinas/genética , Datos de Secuencia Molecular , Mutación , Conformación Proteica , Receptores de Interleucina/genética , Receptores de Interleucina-10/química , Transducción de Señal , Interleucina-22RESUMEN
Interleukin-22 (IL-22) is a class 2 cytokine whose primary structure is similar to that of interleukin 10 (IL-10) and interferon-gamma (IFN-gamma). IL-22 induction during acute phase immune response indicates its involvement in mechanisms of inflammation. Structurally different from IL-10 and a number of other members of IL-10 family, which form intertwined inseparable V-shaped dimers of two identical polypeptide chains, a single polypeptide chain of IL-22 folds on itself in a relatively globular structure. Here we present evidence, based on native gel electrophoresis, glutaraldehyde cross-linking, dynamic light scattering, and small angle x-ray scattering experiments, that human IL-22 forms dimers and tetramers in solution under protein concentrations assessable by these experiments. Unexpectedly, low-resolution molecular shape of IL-22 dimers is strikingly similar to that of IL-10 and other intertwined cytokine dimeric forms. Furthermore, we determine an ab initio molecular shape of the IL-22/IL-22R1 complex which reveals the V-shaped IL-22 dimer interacting with two cognate IL-22R1 molecules. Based on this collective evidence, we argue that dimerization might be a common mechanism of all class 2 cytokines for the molecular recognition with their respective membrane receptor. We also speculate that the IL-22 tetramer formation could represent a way to store the cytokine in nonactive form at high concentrations that could be readily converted into functionally active monomers and dimers upon interaction with the cognate cellular receptors.
Asunto(s)
Interleucinas/química , Receptores de Interleucina/química , Secuencia de Aminoácidos , Reactivos de Enlaces Cruzados/química , Citocinas/química , Citocinas/metabolismo , Dimerización , Electroforesis , Glutaral/química , Humanos , Interleucina-10/química , Interleucina-10/metabolismo , Interleucinas/metabolismo , Datos de Secuencia Molecular , Receptores de Superficie Celular/química , Receptores de Superficie Celular/metabolismo , Receptores de Interleucina/metabolismo , Dispersión de Radiación , Dispersión del Ángulo Pequeño , Difracción de Rayos X , Interleucina-22RESUMEN
Interleukin-22 (IL-22) is a cytokine that regulates the production of acute phase proteins of the immunological response. On binding to its cognate receptor (IL-22R1), which is associated to the interleukin-10 receptor 2 (IL-10R2), IL-22 promotes activation of signal transducer and activator of transcription (STAT) pathway and several other cellular responses. A soluble receptor termed interleukin-22 binding protein (IL-22BP) is also able to bind to IL-22 as a natural protein antagonist, and probably provides systemic regulation of IL-22 activity. This inflammatory response system is analyzed here in terms of its molecular physiology and structural assembly. Three-dimensional (3D) model of IL-22 and structural basis of its interactions with the cognate receptors are discussed.
Asunto(s)
Interleucinas/química , Interleucinas/inmunología , Animales , Bovinos , Cristalografía por Rayos X , Perros , Elefantes , Humanos , Inflamación/inmunología , Macaca mulatta , Ratones , Datos de Secuencia Molecular , Pan troglodytes , Unión Proteica , Conformación Proteica , Ratas , Receptores de Interleucina/inmunología , Alineación de Secuencia , Transducción de Señal/fisiología , Porcinos , Interleucina-22RESUMEN
Interleukin-22 (IL-10-related T cell-derived inducible factor/IL-TIF/IL-22) is a novel cytokine belonging to the IL-10 family. Recombinant human IL-22 (hIL-22) was found to activate the signal transducers and activators of transcription factors 1 and 3 as well as acute phase reactants in several hepatoma cell lines, suggesting its involvement in the inflammatory response. The crystallographic structure of recombinant hIL-22 has been solved at 2.0 A resolution using the SIRAS method. Contrary to IL-10, the hIL-22 dimer does not present an interpenetration of the secondary-structure elements belonging to the two distinct polypeptide chains but results from interface interactions between monomers. Structural differences between these two cytokines, revealed by the crystallographic studies, clearly indicate that, while a homodimer of IL-10 is required for signaling, hIL-22 most probably interacts with its receptor as a monomer.