Defective Gp130-Mediated Signal Transducer and Activator of Transcription (Stat) Signaling Results in Degenerative Joint Disease, Gastrointestinal Ulceration, and Failure of Uterine Implantation

Abstract

The receptor subunit gp130 transduces multiple cell type–specific activities of the leukemia inhibitory factor (LIF)/interleukin (IL)-6 family of cytokines through the signal transducer and activator of transcription (STAT) and src homology 2 domain–bearing protein tyrosine phosphatase (SHP)-2/ras/Erk pathways. To define STAT-dependent physiological responses, we generated mice with a COOH-terminal gp130ΔSTAT “knock-in” mutation which deleted all STAT-binding sites. gp130ΔSTAT mice phenocopyed mice deficient for IL-6 (impaired humoral and mucosal immune and hepatic acute phase responses) and LIF (failure of blastocyst implantation). However, unlike mice with null mutations in any of the components in the gp130 signaling pathway, gp130ΔSTAT mice also displayed gastrointestinal ulceration and a severe joint disease with features of chronic synovitis, cartilaginous metaplasia, and degradation of the articular cartilage. Mitogenic hyperresponsiveness of synovial cells to the LIF/IL-6 family of cyto-kines was caused by sustained gp130-mediated SHP-2/ras/Erk activation due to impaired STAT-mediated induction of suppressor of cytokine signaling (SOCS) proteins which normally limits gp130 signaling. Therefore, the joint pathology in gp130ΔSTAT mice is likely to arise from the disturbance of the otherwise balanced activation of the SHP-2/ras/Erk and STAT signaling cascades emanating from gp130.

Local activation of STAT‐1 and STAT‐3 in the inflamed synovium during zymosan‐induced arthritis: Exacerbation of joint inflammation in STAT‐1 gene–knockout mice

“…These pathways could also be involved in RA (38). Future studies should address their induction by IL-6 and the interplay between these different pathways in arthritis.…”

Regulation and Function of Trefoil Factor Family 3 Expression in the Biliary Tree

“…26,39 In contrast, mice with a mutation selectively abrogating only SHP-2-Ras-ERK (MAPK) signaling (gp130 757F ) were resistant to colitis, but developed gastric adenomas as a consequence of unopposed STAT3 signaling. 26,39 A conclusion of these detailed Figure 8. Immunohistochemical staining for TFF3 protein in mouse liver at 12 weeks after BDL showed expression was exclusively limited to the large bile ducts and peribiliary glands (inset) in IL-6 ϩ/ϩ mouse liver (A), but weakly present in the large bile ducts in IL-6 Ϫ/Ϫ (B) mouse liver.…”

“…15,16,28,42 Trefoil peptides also enhance intestinal epithelial restitution primarily by stimulating epithelial cell spreading and migration, which accelerates mucosal epithelial recovery after injury. 40,43 Each of the TFF proteins is differentially regulated in different parts of the gastrointestinal tract: 26,39 TFF1 and TFF2 are expressed primarily in the stomach 44,45 and TFF3 predominates in the small and large intestines. 41 In the liver, this and previous studies have shown that TFF1 and TFF3 are constitutively expressed in the large bile ducts of mouse and human livers.…”

“…26,39 Mice harboring mutations that selectively block all gp130-mediated STAT activity (gp130⌬ STAT ), but preserve gp130-mediated MAPK signaling show decreased colonic TFF3 expression, increased sensitivity to sodium dextran sulfate-induced colitis, and impaired mucosal wound healing. 26,39 In contrast, mice with a mutation selectively abrogating only SHP-2-Ras-ERK (MAPK) signaling (gp130 757F ) were resistant to colitis, but developed gastric adenomas as a consequence of unopposed STAT3 signaling. 26,39 A conclusion of these detailed Figure 8.…”

The IL-27 Receptor (WSX-1) Is an Inhibitor of Innate and Adaptive Elements of Type 2 Immunity

“…Therefore, it is now clear that lymphoid and nonlymphoid cell types express a functional IL-27R (i.e., WSX-1 and gp130), and that the functions of this dimeric receptor are not restricted to the regulation of T cell activity. The recognition that gp130, a receptor chain that has been linked to the suppression of inflammation (44,45), forms part of the IL-27R complex supports an inhibitory role for IL-27. Thus, IL-27/IL-27R interactions may provide a general mechanism to down-regulate immune activity in multiple hemopoietic cell types.…”