title: Pentoxifylline inhibits certain constitutive and tumor necrosis factor-alpha-induced activities of human normal dermal fibroblasts.
abstract: Pentoxifylline (PFN), analog of theobromine, which phenotypically and functionally alters various cell types including dermal fibroblasts, has been reported to inhibit tumor necrosis factor-alpha (TNF alpha) activation of neutrophils. We investigated the ability of PFN to alter constitutive and TNF alpha-induced biosynthetic activities of human normal dermal fibroblasts. The sixteenfold increase over constitutive intracellular 2'-5' oligo-adenylate synthetase (2'-5' A synthetase) activity induced by TNF alpha (400 U/ml) failed to occur when PFN (1 mg/ml) was added prior to cytokine treatment. This loss of biologic activity paralleled a reduction in 2'-5' A synthetase proteins and 2'-5' A synthetase-specific m-RNA. PFN failed to inhibit constitutive or TNF alpha-induced IL-6 hybridoma proliferative activity, IL-6 protein, or IL-6-specific m-RNA levels. The presence of PFN (1 mg/ml) in fibroblast cultures reduced constitutive synthesis of collagen and glycosaminoglycan (GAG) by 87% and 45%, respectively, and blocked induction of their synthesis by TNF alpha (10(4) U/ml). Total non-collagenous protein synthesis was not inhibited following PFN treatment (1 mg/ml). PFN did not inhibit TNF alpha induction of only those biosynthetic activities also susceptible to PFN in the constitutive state, with PFN failing to reduce constitutive collagenolytic activity but reducing TNF alpha-induced enhanced collagenolytic activity by 26% and collagenase m-RNA by 51%. Furthermore, PFN did inhibit, by 98%, TNF alpha-dependent murine and human fibroblast cytotoxicity. The selective nature of PFN inhibition of certain TNF alpha activities, the failure of PFN (1 mg/ml) to alter constitutive and TNF alpha-induced levels of type 1 and 2 TNF alpha receptor m-RNA, and the finding that PFN-treated fibroblasts express a similar number of receptors, of similar molecular weight and high affinity for TNF alpha as control, untreated cells, suggest that inhibitory activities of PFN are mediated at a locus other than receptors for TNF alpha.
authors.affiliation: Department of Dermatology, University of California, Davis School of Medicine.
authors.forename: B
authors.initials: B
authors.lastname: Berman
authors.forename: J
authors.initials: J
authors.lastname: Wietzerbin
authors.forename: J
authors.initials: J
authors.lastname: Sanceau
authors.forename: G
authors.initials: G
authors.lastname: Merlin
authors.forename: M R
authors.initials: MR
authors.lastname: Duncan
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000096:biosynthesis; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D003012:Microbial Collagenase / Q000235:genetics; D010431:Pentoxifylline / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor; D012867:Skin / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D006025:Glycosaminoglycans; D015850:Interleukin-6; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D015088:2',5'-Oligoadenylate Synthetase; D003012:Microbial Collagenase; D010431:Pentoxifylline