Specifically, knockout or neutralization of IL‐36γ or administration of IL‐36Ra significantly inhibited the expression of cell‐matrix adhesion molecules such as Vwf, Col4a1, and Col6a1, whereas knockout of IL‐36Ra had opposite effects in DSS colitis and colon cancer models, indicating that the agonistic and antagonistic IL‐36R signaling reciprocally controls extracellular matrix network for pro‐ and anti‐inflammation and tumorigenesis in the gastrointestinal system, respectively. The gene discussed is COL4A1; the disease is colonic neoplasm.