TY - JOUR
T1 - TNF-anti-TNF immune complexes inhibit IL-12/IL-23 secretion by inflammatory macrophages via an fc-dependent mechanism
AU - Bloemendaal, Felicia M.
AU - Koelink, Pim J.
AU - van Schie, Karin A.
AU - Rispens, Theo
AU - Peters, Charlotte P.
AU - Buskens, Christianne J.
AU - van der Bilt, Jarmila D.
AU - Bemelman, Willem A.
AU - Korf, Hannelie
AU - Sabino, João G.
AU - Ponsioen, Cyriel Y.
AU - te Velde, Anje A.
AU - D'Haens, Geert R. A. M.
AU - Vermeire, Severine
AU - van den Brink, Gijs R.
AU - Wildenberg, Manon E.
PY - 2018
Y1 - 2018
N2 - Background and Aims We have recently shown that the mode of action of IgG1 anti-tumour necrosis factor [TNF] antibodies in inflammatory bowel disease [IBD] requires Fcγ-receptor [FcγR] engagement on macrophages. Here we examine the effect of Fcγ-receptor signalling by anti-TNF on macrophage IL-12/IL-23 secretion. Methods Cytokine production by human inflammatory macrophages was assessed at the level of RNA and protein. TNF-anti-TNF immune complex formation was determined by size-exclusion chromatography and signalling visualized by immunofluorescence. IL-12/IL-23p40 was measured in CD14+ lamina propria cells from IBD patients. Results Infliximab and adalimumab potently suppressed IL-12/IL-23 production by inflammatory macrophages, but Fab' fragment certolizumab did not. IL-12/IL-23 suppression depended on Syk activity and was mediated at the level of IL-12/IL-23p40 mRNA. Etanercept, a soluble TNF receptor fused to an Fc-region, did not inhibit IL-12/L-23 secretion, suggesting that the presence of an Fc-region was not sufficient. Infliximab and adalimumab formed immune complexes with soluble TNF whereas etanercept did not, suggesting that FcγR-mediated suppression of IL-12/IL-23 required the formation of immune complexes. Indeed, non-specific IgG1 immune complexes, but not uncomplexed IgG1, similarly suppressed IL-12/IL-23 secretion. Finally, infliximab significantly decreased IL-12/IL-23p40 production in myeloid cells isolated from the lamina propria of IBD patients. Conclusions TNF-anti-TNF antibody immune complexes potently inhibit IL-12/IL-23 expression by inflammatory macrophages. Our data suggest that anti-TNFs and antibodies against IL-12/IL-23 may therefore have partially overlapping modes of action in patients with IBD.
AB - Background and Aims We have recently shown that the mode of action of IgG1 anti-tumour necrosis factor [TNF] antibodies in inflammatory bowel disease [IBD] requires Fcγ-receptor [FcγR] engagement on macrophages. Here we examine the effect of Fcγ-receptor signalling by anti-TNF on macrophage IL-12/IL-23 secretion. Methods Cytokine production by human inflammatory macrophages was assessed at the level of RNA and protein. TNF-anti-TNF immune complex formation was determined by size-exclusion chromatography and signalling visualized by immunofluorescence. IL-12/IL-23p40 was measured in CD14+ lamina propria cells from IBD patients. Results Infliximab and adalimumab potently suppressed IL-12/IL-23 production by inflammatory macrophages, but Fab' fragment certolizumab did not. IL-12/IL-23 suppression depended on Syk activity and was mediated at the level of IL-12/IL-23p40 mRNA. Etanercept, a soluble TNF receptor fused to an Fc-region, did not inhibit IL-12/L-23 secretion, suggesting that the presence of an Fc-region was not sufficient. Infliximab and adalimumab formed immune complexes with soluble TNF whereas etanercept did not, suggesting that FcγR-mediated suppression of IL-12/IL-23 required the formation of immune complexes. Indeed, non-specific IgG1 immune complexes, but not uncomplexed IgG1, similarly suppressed IL-12/IL-23 secretion. Finally, infliximab significantly decreased IL-12/IL-23p40 production in myeloid cells isolated from the lamina propria of IBD patients. Conclusions TNF-anti-TNF antibody immune complexes potently inhibit IL-12/IL-23 expression by inflammatory macrophages. Our data suggest that anti-TNFs and antibodies against IL-12/IL-23 may therefore have partially overlapping modes of action in patients with IBD.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85055794891&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29860435
U2 - https://doi.org/10.1093/ecco-jcc/jjy075
DO - https://doi.org/10.1093/ecco-jcc/jjy075
M3 - Article
C2 - 29860435
SN - 1873-9946
VL - 12
SP - 1122
EP - 1130
JO - Journal of Crohn s & colitis
JF - Journal of Crohn s & colitis
IS - 9
ER -