title: STAT3, p38 MAPK, and NF-kappaB drive unopposed monocyte-dependent fibroblast MMP-1 secretion in tuberculosis.
abstract: Tissue destruction characterizes infection with Mycobacterium tuberculosis (Mtb). Type I collagen provides the lung's tensile strength, is extremely resistant to degradation, but is cleaved by matrix metalloproteinase (MMP)-1. Fibroblasts potentially secrete quantitatively more MMP-1 than other lung cells. We investigated mechanisms regulating Mtb-induced collagenolytic activity in fibroblasts in vitro and in patients. Lung fibroblasts were stimulated with conditioned media from Mtb-infected monocytes (CoMTb). CoMTb induced sustained increased MMP-1 (74 versus 16 ng/ml) and decreased tissue inhibitor of metalloproteinase (TIMP)-1 (8.6 versus 22.3 ng/ml) protein secretion. CoMTb induced a 2.7-fold increase in MMP-1 promoter activation and a 2.5-fold reduction in TIMP-1 promoter activation at 24 hours (P = 0.01). Consistent with this, TIMP-1 did not co-localize with fibroblasts in patient granulomas. MMP-1 up-regulation and TIMP-1 down-regulation were p38 (but not extracellular signal-regulated kinase or c-Jun N-terminal kinase) mitogen-activated protein kinase-dependent. STAT3 phosphorylation was detected in fibroblasts in vitro and in tuberculous granulomas. STAT3 inhibition reduced fibroblast MMP-1 secretion by 60% (P = 0.046). Deletion of the MMP-1 promoter NF-κB-binding site abrogated promoter induction in response to CoMTb. TNF-α, IL-1β, or Oncostatin M inhibition in CoMTb decreased MMP-1 secretion by 65, 63, and 25%, respectively. This cytokine cocktail activated the same signaling pathways in fibroblasts and induced MMP-1 secretion similar to that induced by CoMTb. This study demonstrates in a cellular model and in patients with tuberculosis that in addition to p38 and NF-κB, STAT3 has a key role in driving fibroblast-dependent unopposed MMP-1 production that may be key in tissue destruction in patients.
authors.affiliation: Department of Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London, London, United Kingdom.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: O'Kane
authors.forename: Paul T
authors.initials: PT
authors.lastname: Elkington
authors.forename: Michael D
authors.initials: MD
authors.lastname: Jones
authors.forename: Luz
authors.initials: L
authors.lastname: Caviedes
authors.forename: Marco
authors.initials: M
authors.lastname: Tovar
authors.forename: Robert H
authors.initials: RH
authors.lastname: Gilman
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.forename: Jon S
authors.initials: JS
authors.lastname: Friedland
mesh_terms: D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014376:Tuberculosis / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D053583:Interleukin-1beta; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D048051:p38 Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1