biostudies-literatureZhang ZZNIH Oxford-Cambridge and Harvard Medical School Medical Scientist Training ProgramIntramural Research Program of NIH, National Institute of Allergy and Infectious DiseasesSanming Project of Medicine in Shenzhene2009217118https://www.ebi.ac.uk/biostudies/studies/S-EPMC7958356biostudies-literatureUnknown118(10)Interleukin (IL)-37, an antiinflammatory IL-1 family cytokine, is a key suppressor of innate immunity. IL-37 signaling requires the heterodimeric IL-18R1 and IL-1R8 receptor, which is abundantly expressed in the gastrointestinal tract. Here we report a 4-mo-old male from a consanguineous family with a homozygous loss-of-function IL37 mutation. The patient presented with persistent diarrhea and was found to have infantile inflammatory bowel disease (I-IBD). Patient cells showed increased intracellular IL-37 expression and increased proinflammatory cytokine production. In cell lines, mutant IL-37 was not stably expressed or properly secreted and was thus unable to functionally suppress proinflammatory cytokine expression. Furthermore, induced pluripotent stem cell-derived macrophages from thProceedings of the National Academy of Sciences of the United States of AmericaHomozygous IL37 mutation associated with infantile inflammatory bowel disease.PMC7958356N/ASZSM201812002Gonzaga-Jauregui COzen AZhang ZZKarakoc-Aydiner EBaris SLenardo MJSweeney CLHe TYao YSmith KGCZhang YMalech HLMatthews HFErtem DSu HCfalseHomozygous IL37 mutation associated with infantile inflammatory bowel disease.Interleukin (IL)-37, an antiinflammatory IL-1 family cytokine, is a key suppressor of innate immunity. IL-37 signaling requires the heterodimeric IL-18R1 and IL-1R8 receptor, which is abundantly expressed in the gastrointestinal tract. Here we report a 4-mo-old male from a consanguineous family with a homozygous loss-of-function IL37 mutation. The patient presented with persistent diarrhea and was found to have infantile inflammatory bowel disease (I-IBD). Patient cells showed increased intracellular IL-37 expression and increased proinflammatory cytokine production. In cell lines, mutant IL-37 was not stably expressed or properly secreted and was thus unable to functionally suppress proinflammatory cytokine expression. Furthermore, induced pluripotent stem cell-derived macrophages from th2021-01-01T00:00:00Z2021 Mar2025-04-19T15:37:21.754Z2025-04-19T15:37:21.754ZS-EPMC79583563367438010.1073/pnas.2009217118