title: Therapeutic potential of chloroquine in a murine model of inflammatory bowel disease.
abstract: Inflammatory bowel disease (IBD) is an idiopathic chronic inflammation of the gastrointestinal tract which is mainly caused by dysregulated gut immune response to commensal flora. Very limited treatment options with marginal efficacy are available along with surgery which has high risk of reoccurrence. As both innate and adaptive immune responses have been found altered in IBD, a good therapeutic strategy could be to restrict both of them under chronic inflammatory conditions. Effect of chloroquine on TLR9 signaling is well reported, while there are limited studies on non-endosomal TLRs as well as T cell responses. Hence, we studied its effect on other TLRs as well as T cell response along with testing it as a potential therapeutics in IBD using murine preclinical colitis model. Chloroquine significantly suppressed the TLR2 as well as TLR9 signaling in both in vitro as well as in vivo experimental settings, while it had no effect on TLR4 pathway. It also suppressed the T cell cytokine and proliferative responses. In, DSS-induced murine colitis model, chloroquine administration, significantly improved body weight loss, colon length shortening, tissue damage and inflammatory cell infiltration. Based on our findings in preclinical murine model of IBD, chloroquine has the potential to be considered as a therapeutic option in clinics through inhibition of diverse TLR and T cell responses.
authors.affiliation: Syngene International Limited, Biology (In Vivo), Biocon-Bristol Myers Squibb Research & Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Jignesh
authors.initials: J
authors.lastname: Nagar
authors.affiliation: Syngene International Limited, Biology (In Vivo), Biocon-Bristol Myers Squibb Research & Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Sourabh
authors.initials: S
authors.lastname: Ranade
authors.affiliation: Syngene International Limited, Biology (In Vivo), Biocon-Bristol Myers Squibb Research & Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Vinay
authors.initials: V
authors.lastname: Kamath
authors.affiliation: Syngene International Limited, Biology (In Vivo), Biocon-Bristol Myers Squibb Research & Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Sharad
authors.initials: S
authors.lastname: Singh
authors.affiliation: Syngene International Limited, Biology (In Vivo), Biocon-Bristol Myers Squibb Research & Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Preethi
authors.initials: P
authors.lastname: Karunanithi
authors.affiliation: Syngene International Limited, Biology (In Vivo), Biocon-Bristol Myers Squibb Research & Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Siva
authors.initials: S
authors.lastname: Subramani
authors.affiliation: Syngene International Limited, Biology (In Vivo), Biocon-Bristol Myers Squibb Research & Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Kamala
authors.initials: K
authors.lastname: Venkatesh
authors.affiliation: Syngene International Limited, Biology (In Vivo), Biocon-Bristol Myers Squibb Research & Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Ratika
authors.initials: R
authors.lastname: Srivastava
authors.affiliation: Syngene International Limited, Biology (In Vivo), Biocon-Bristol Myers Squibb Research & Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Shailesh
authors.initials: S
authors.lastname: Dudhgaonkar
authors.affiliation: Bristol-Myers Squibb India Pvt. Ltd., Biology (In Vivo), Biocon-Bristol Myers Squibb Research & Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India. Electronic address: reeba.vikramadithyan@bms.com.
authors.forename: Reeba Kannimel
authors.initials: RK
authors.lastname: Vikramadithyan
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D003092:Colitis / Q000188:drug therapy / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: D016207:Cytokines; C493486:Tlr2 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9; D002738:Chloroquine
keywords: Chloroquine; DSS-induced colitis; Inflammatory bowel disease; Toll-like receptor