title: IL12p40 regulates functional development of human CD4+ T cells: enlightenment by the elevated expressions of IL12p40 in patients with inflammatory bowel diseases.
abstract: The proinflammatory effects of IL12p40 had been documented in the literature, and anti-IL12p40 treatment had been proved to be effective in therapy of Crohn disease (CD) in a phase 2b clinical trial. However, the precise role of IL12p40 in the pathogenesis of inflammatory bowel disease (IBD) was still poorly understood. In this study, we investigated the expressions of IL12p40 and its receptor interleukin-12 receptor β 1 both locally and systemically in IBD cases and healthy controls, and the contribution of IL12p40 in IBD pathogenesis. We found that the expression of IL12p40 was elevated both at messenger RNA and protein levels systematically and locally in IBD patients but more significantly in CD patients. Our genetic association study revealed that the polymorphisms of IL12B rs6887695 were associated with both CD and ulcerative colitis (UC) susceptibility in Chinese population, but did not affect the serum IL12p40 level in either CD patients or UC patients. In addition, CD4⁺ T cells isolated from peripheral blood of CD patients secreted the most abundant IL12p40 production, compared with the UC patients and healthy controls. We also found for the first time that neutralizing IL12p40 secretion could inhibit proliferation, enhance apoptosis, induce a G0/G1 arrest, restrain T helper 1 type immune responses, and promote chemokine C-C motif ligand 20-mediated migration of human CD4⁺ T cells, which might be the mechanisms why anti-IL12p40 treatment presented efficacy in CD.
authors.affiliation: From the Department of Gastroenterology/Hepatology (XW, TW, F Zhou, SL, RZ, SZ, LS, F Zhu, GW, BX), Zhongnan Hospital of Wuhan University; and The Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases (XW, TW, SL, RZ, SZ, LS, F Zhu, GW, BX), Wuhan, Hubei, PR China.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Wang
authors.forename: Ting
authors.initials: T
authors.lastname: Wu
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.forename: Shi
authors.initials: S
authors.lastname: Liu
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.forename: Siying
authors.initials: S
authors.lastname: Zhu
authors.forename: Lu
authors.initials: L
authors.lastname: Song
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.forename: Ge
authors.initials: G
authors.lastname: Wang
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics; D015704:CD4 Antigens / Q000097:blood*; D049109:Cell Proliferation; D003093:Colitis, Ulcerative / Q000097:blood; D003424:Crohn Disease / Q000097:blood; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000097:blood* / Q000235:genetics; D053762:Interleukin-12 Subunit p40 / Q000097:blood* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D015854:Up-Regulation / Q000502:physiology; D055815:Young Adult
chemical_list: D015704:CD4 Antigens; D053762:Interleukin-12 Subunit p40; D012333:RNA, Messenger