Pentoxifylline Inhibits Certain Constitutive and Tumor Necrosis Factor-α-Induced Activities of Human Normal Dermal Fibroblasts

Pentoxifylline (PFN), an analog of theobromine, which phenotypically and functionally alters various cell types including dermal fibroblasts, has been reported to inhibit tumor necrosis factor-α (TNFα activation of neutrophils. We investigated the ability of PFN to alter constitutive and TNFα 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 TNFα (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 TNFα-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 glycosaminogylcan (GAG) by 87% and 45%, respectively, and blocked induction of their synthesis by TNFα (104 U/ml).Total non-collagenous protein synthesis was not inhibited following PFN treatment (1 mg/ml). PFN did not inhibit TNFα induction of only those biosynthetic activities also susceptible to PFN in the constitutive state, with PFN failing to reduce constitutive collagenolytic activity but reducing TNFα-induced enhanced collagenolytic activity by 26% and collagenase m-RNA by 51%. Furthermore, PFN did inhibit, by 98%, TNFα-dependent murine and human fibroblast cytotoxicity.The selective nature of PFN inhibition of certain TNFα activities, the failure of PFN (1 mg/ml) to alter constitutive and TNFα-induced levels of type 1 and 2 TNFα receptor m-RNA, and the finding that PFN-treated fibroblasts express a similar number of receptors, of similar molecular weight and high affinity for TNFα as control, untreated cells, suggest that inhibitory activities of PFN are mediated at a locus other than receptors for TNFα