Polyinosine-polycytidylic acid stimulates versican accumulation in the extracellular matrix promoting monocyte adhesion.
Viral infections are known to exacerbate asthma and other lung diseases in which chronic inflammatory processes are implicated, but the mechanism is not well understood. The viral mimetic, polyinosine-polycytidylic acid, causes accumulation of a versican- and hyaluronan-enriched extracellular matrix (ECM) by human lung fibroblasts with increased capacity for monocyte adhesion. The fivefold increase in versican retention in this ECM is due to altered compartmentalization, with decreased degradation of cell layer-associated versican, rather than an increase in total accumulation in the culture. This is consistent with decreased mRNA levels for all of the versican splice variants. Reduced versican degradation is further supported by low levels of the epitope, DPEAAE, a product of versican digestion by a disintegrin-like and metallopeptidase with thrombospondin type 1 motif enzymes, in the ECM. The distribution of hyaluronan is similarly altered with a 3.5-fold increase in the cell layer. Pulse-chase studies of radiolabeled hyaluronan show a 50% reduction in the rate of loss from the cell layer over 24 hours. Formation of monocyte-retaining, hyaluronidase-sensitive ECMs can be blocked by the presence of anti-versican antibodies. In comparison, human lung fibroblasts treated with the cytokines, IL-1beta plus TNF-alpha, synthesize increased amounts of hyaluronan, but do not retain it or versican in the ECM, which, in turn, does not retain monocytes. These results highlight an important role for versican in the hyaluronan-dependent binding of monocytes to the ECM of lung fibroblasts stimulated with polyinosine-polycytidylic acid.
Potter-Perigo
Susan
S
Hope Heart Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101-2795, USA.
Johnson
Pamela Y
PY
Evanko
Stephen P
SP
Chan
Christina K
CK
Braun
Kathleen R
KR
Wilkinson
Thomas S
TS
Altman
Leonard C
LC
Wight
Thomas N
TN
D002448:Cell Adhesion; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D000939:Epitopes / Q000737:chemistry; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000473:pathology; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D011066:Poly C / Q000378:metabolism*; D011069:Poly I / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019699:Thrombospondins / Q000737:chemistry / Q000378:metabolism; D053675:Versicans / Q000378:metabolism*
D000939:Epitopes; D053583:Interleukin-1beta; D019699:Thrombospondins; D053675:Versicans; D011069:Poly I; D011066:Poly C; D006820:Hyaluronic Acid