title: Therapeutic Effect of Recombinant Mutated Interleukin 11 in the Mouse Model of Tuberculosis.
abstract: Earlier we demonstrated that blocking of interleukin 11 (IL-11) by systemic administration of anti-IL-11 antibodies attenuates severity of Mycobacterium tuberculosis infection in mice. The substitution W147A in the IL-11 molecule creates the form of cytokine capable to disrupt gp130/IL11R signaling complex formation, thus serving as a high-affinity specific antagonist of IL-11-mediated signaling. We hypothesized that this mutant form of IL-11 may serve as an effective tool for inhibition of native IL-11 activity in vivo. We established the recombinant W147A mutant form of IL-11 in an optimized Escherichia coli expression system and administered it as the aerosol in the lungs of M. tuberculosis-susceptible I/St mice infected with M. tuberculosis Our results show that this therapeutic approach markedly inhibits tuberculous inflammation in lungs, increases the survival time of infected animals, and decreases expression of key inflammatory factors at the RNA and protein levels. These findings are a step toward clinical evaluation of the anti-IL-11 therapy for tuberculosis.
authors.affiliation: Laboratory for Immunogenetics, Central Institute for Tuberculosis, Moscow, Russia.
authors.forename: Galina
authors.initials: G
authors.lastname: Shepelkova
authors.affiliation: Laboratory for Immunogenetics, Central Institute for Tuberculosis, Moscow, Russia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Evstifeev
authors.affiliation: Laboratory for Immunogenetics, Central Institute for Tuberculosis, Moscow, Russia.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Majorov
authors.affiliation: Laboratory for Immunogenetics, Central Institute for Tuberculosis, Moscow, Russia.
authors.forename: Irina
authors.initials: I
authors.lastname: Bocharova
authors.affiliation: Laboratory for Immunogenetics, Central Institute for Tuberculosis, Moscow, Russia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Apt
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D019943:Amino Acid Substitution; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D007155:Immunologic Factors / Q000008:administration & dosage*; D007249:Inflammation / Q000473:pathology; D017370:Interleukin-11 / Q000037:antagonists & inhibitors*; D008168:Lung / Q000473:pathology; D051379:Mice; D050505:Mutant Proteins / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000008:administration & dosage*; D016019:Survival Analysis; D045506:Therapeutic Uses; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
chemical_list: D000336:Aerosols; D007155:Immunologic Factors; D017370:Interleukin-11; D050505:Mutant Proteins; D011994:Recombinant Proteins; D045506:Therapeutic Uses
keywords: IL-11; inflammation; mouse model; tuberculosis