Hyper-inflammation and skin destruction mediated by rosiglitazone activation of macrophages in IL-6 deficiency. J Invest Dermatol 2015 Feb;135(2):389-399
Date
09/04/2014Pubmed ID
25184961Pubmed Central ID
PMC4291681DOI
10.1038/jid.2014.375Scopus ID
2-s2.0-84930182637 (requires institutional sign-in at Scopus site) 13 CitationsAbstract
Injury initiates recruitment of macrophages to support tissue repair; however, excessive macrophage activity may exacerbate tissue damage causing further destruction and subsequent delay in wound repair. Here we show that the peroxisome proliferation-activated receptor-γ agonist, rosiglitazone (Rosi), a medication recently reintroduced as a drug to treat diabetes and with known anti-inflammatory properties, paradoxically generates pro-inflammatory macrophages. This is observed in both IL-6-deficient mice and control wild-type mice experimentally induced to produce high titers of auto-antibodies against IL-6, mimicking IL-6 deficiency in human diseases. IL-6 deficiency when combined with Rosi-mediated upregulation of suppressor of cytokine signaling 3 leads to an altered ratio of nuclear signal transducer and activator of transcription 3/NF-κB that allows hyper-induction of inducible nitric oxide synthase (iNOS). Macrophages activated in this manner cause de novo tissue destruction, recapitulating human chronic wounds, and can be reversed in vivo by recombinant IL-6, blocking macrophage infiltration, or neutralizing iNOS. This study provides insight into an unanticipated paradoxical role of Rosi in mediating hyper-inflammatory macrophage activation significant for diseases associated with IL-6 deficiency.
Author List
Das LM, Rosenjack J, Au L, Galle PS, Hansen MB, Cathcart MK, McCormick TS, Cooper KD, Silverstein RL, Lu KQAuthor
Roy L. Silverstein MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsFemale
Inflammation
Interleukin-6
Macrophage Activation
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
NF-kappa B
Nitric Oxide Synthase Type II
STAT3 Transcription Factor
Skin
Thiazolidinediones
Wound Healing
