Epithelial gp130/Stat3 functions: An intestinal signaling node in health and disease

• Epithelial Stat3 signaling promotes wound-healing of the gastrointestinal lining.
• Aberrant gp130/Stat3 signaling supports the growth of gastric and intestinal tumors.
• Interleukin-11 is a more potent driver of gastrointestinal tumorigenesis than IL6.
• Therapeutic interference with IL11 signaling blocks gastrointestinal tumor growth.

A contiguous intestinal epithelial barrier safeguards against aberrant activation of the immune system and therefore requires molecular mechanisms that ensure effective wound-healing responses. During this processes cytokine-producing myeloid cells serve as rheostats that link the degree of wounding and local inflammation to the epithelial repair response. Likewise, intestinal inflammation is an important factor by which the microenvironment promotes tumorigenesis and the progression of established cancers by facilitating neoplastic cell survival and proliferation. Among the cytokines and chemokines orchestrating this process, those comprising the interleukin (IL) IL6, IL10/IL22 and IL17/IL23 families play a prominent role by virtue of converging on the latent Signal Transducer and Activator of Transcription (Stat)-3. Accordingly, aberrant and persistent Stat3 activation is a frequent observation in cancers of the gastrointestinal tract where it promotes “cancer hallmark capabilities” in the malignant epithelium and suppresses the anti-tumor response of innate and adaptive immune cells. Here, we discuss recent insights arising from situations where persistent activation of the gp130/Stat3 signaling cascades result from excessive abundance of IL6 family cytokines. In particular, we highlight novel and unique roles for IL11 in promoting intestinal wound-healing and, in its corrupted form, enabling and facilitating growth of inflammation-associated and sporadic gastrointestinal tumors.