Involvement of the nuclear factor-κB pathway in the pathogenesis of endometriosis  Reinaldo González-Ramos, M.D., Ph.D., Anne Van Langendonckt, Ph.D., Sylvie Defrère, Ph.D., Jean-Christophe Lousse, M.D., Sebastien Colette, B.Sc., Luigi Devoto, M.D., Jacques Donnez, M.D., Ph.D.  Fertility and Sterility  Volume 94, Issue 6, Pages 1985-1994 (November 2010) DOI: 10.1016/j.fertnstert.2010.01.013 Copyright © 2010 American Society for Reproductive Medicine Terms and Conditions

Figure 1 Nuclear factor-κB (NF-κB) subunits and dimers and IκBα protein. RHD: Rel homology domain, responsible for DNA binding, dimerization, and association with IκB proteins; TAD: transcriptional activation domain; AR: ankyrin repeats, responsible for cytoplasmic retention and inhibition of NF-κB (preventing DNA binding). Peptides p50 and p52 derive from precursor proteins p105 and p100 and lack a TAD. Dimers in the fifth row therefore lack TADs. Dimers in the final row are not able to bind to DNA. Adapted from references (41) and (42). Fertility and Sterility 2010 94, 1985-1994DOI: (10.1016/j.fertnstert.2010.01.013) Copyright © 2010 American Society for Reproductive Medicine Terms and Conditions

Figure 2 Nuclear factor-κB (NF-κB) activation pathways. UV: ultraviolet radiation; LTβR: lymphotoxin-β receptor; BAFF: B-cell-activating factor of the tumor necrosis factor (TNF) family; LMP1: latent membrane protein-1; Tyr K: tyrosine kinase; CK2: casein kinase-II; P: phosphorylation; UB: ubiquitination; NIK: NF-κB-inducing kinase. Adapted from references (30) and (43). Fertility and Sterility 2010 94, 1985-1994DOI: (10.1016/j.fertnstert.2010.01.013) Copyright © 2010 American Society for Reproductive Medicine Terms and Conditions

Figure 3 Nuclear factor-κB (NF-κB) activation in endometriosis. Activated macrophages secrete cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), which activate NF-κB in endometriotic cells (EcCs) and macrophages, amplifying the inflammatory response. Iron overload in the peritoneal cavity and in peritoneal macrophages may impair macrophage phagocytic function and activate NF-κB. Iron could also activate NF-κB in EcCs. NF-κB activation in EcCs enhances synthesis of proinflammatory mediators as well as factors of antiapoptosis, growth, invasion, and angiogenesis. NF-κB transcriptional activity could also be responsible for ICAM-1 and RANTES expression and secretion, attracting more macrophages to sites of inflammation. Fertility and Sterility 2010 94, 1985-1994DOI: (10.1016/j.fertnstert.2010.01.013) Copyright © 2010 American Society for Reproductive Medicine Terms and Conditions