Molecular effects of recombinant human interleukin-11 in the HLA-B27 rat model of inflammatory bowel disease.
Recombinant human interleukin-11 (rhIL-11) is a pleiotropic cytokine with effects on multiple cell types. In addition to thrombopoietic activity, rhIL-11 has demonstrated anti-inflammatory activity in vitro and in vivo. rhIL-11 treatment reduces clinical signs and histologic lesions of colitis in transgenic rats expressing the human major histocompatibility complex (MHC) Class I allele, HLA-B27. We have investigated the effects of rhIL-11 at the molecular and cellular level in this model of inflammatory bowel disease. RT-PCR analysis of colonic RNA revealed that treatment with rhIL-11 down-regulated expression of proinflammatory cytokines including TNF-alpha, IL-1beta, and IFN-gamma. rhIL-11 also reduced the level of myeloperoxidase activity in the cecum indicating reduced inflammation. After stimulation in vitro with anti-CD3 antibody, spleen cell cultures derived from rhIL-11-treated rats produced less IFN-gamma, TNF-alpha, and IL-2 than cultures derived from vehicle-treated rats. These molecular and cellular effects correlated with amelioration of disease as measured by stool character and histologic lesion scores. These findings suggest that rhIL-11 acts to reduce inflammation through modulation of multiple proinflammatory mediators including products of activated T cells. This study has identified pharmacodynamic markers of rhIL-11 anti-inflammatory activity in vivo and supports rhIL-11 therapy to treat inflammatory bowel disease.
Peterson
R L
RL
Preclinical Research and Development, Genetics Institute, Andover, Massachusetts 01810, USA.
Wang
L
L
Albert
L
L
Keith
J C
JC
Dorner
A J
AJ
D000818:Animals; D030801:Animals, Genetically Modified; D002432:Cecum / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005805:Genes, MHC Class I; D015796:HLA-B27 Antigen / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics; D017370:Interleukin-11 / Q000494:pharmacology*; D007378:Interleukins / Q000235:genetics; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000494:pharmacology*; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D001613:beta 2-Microglobulin / Q000235:genetics / Q000502:physiology
D016207:Cytokines; D015796:HLA-B27 Antigen; D017370:Interleukin-11; D007378:Interleukins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D001613:beta 2-Microglobulin; D007371:Interferon-gamma