Abstract. Interleukin-I (IL-1) is synthesized by and released from macrophages in response to a variety of stimuli and appears to play an essential role in virtually all inflammatory conditions. In tissues of mesenchymal origin (e.g., cartilage, muscle, bone, and soft connective tissue) ILl induces changes characteristic of both destructive as well as reparative phenomena. Previous studies with natural IL-1 of varying degrees of purity have suggested that it is capable of modulating a number of biological activities of fibroblasts. We have compared the effects of purified human recombinant (hr) IL-la and !~ on several fibroblast functions. The parameters studied include cell proliferation, chemotaxis, and production of collagen, collagenase, tissue inhibitor of metalloproteinase (TIMP), and prostaglandin (PG) E2. We observed that hrlL-ls stimulate the synthesis and accumulation of type I procollagen chains. Intracellular degradation of collagen is not altered by the hrlL-ls. Both IL-ls were observed to increase the steady-state levels of pro al(I) and pro a2(I) mRNAs, indicating that they exert control of type I procollagen gene expression at the pretranslational level. We found that both hrlL-la and 13 stimulate synthesis of TIMP, collagenase, PGE2, and growth of fibroblasts in vitro but are not chemotactic for fibroblasts. Although hrlL-la and 13 both are able to stimulate production of PGE2 by fibroblasts, inhibition of prostaglandin synthesis by indomethacin has no measurable effect on the ability of the IL-ls to stimulate cell growth or production of collagen and collagenase. Each of the IL-ls stimulated proliferation and collagen production by fibroblasts to a similar degree, however hrlL-113 was found to be less potent than hrlL-1 a in stimulating PGE2 production. These observations support the notion that IL-l~t and 13 may both modulate the degradation of collagen at sites of tissue injury by virtue of their ability to stimulate collagenase and PGE2 production by fibroblasts. Furthermore, IL-la and 13 might also direct reparative functions of fibroblasts by stimulating their proliferation and synthesis of collagen and TIMP.

Tumor necrosis factor-alpha (TNF-alpha) has recently been implicated as a cause of insulin resistance (IR) in obesity and non-insulin dependent diabetes mellitus (NIDDM). To examine mechanisms involved, we induced IR induced IR in H-411 E cells with graded doses of TNF-alpha and measured the ability of insulin (INS) to stimulate both calmodulin (CaM) mRNA and glucose utilization. With TNF-alpha concentration at 1 ng/ml and 10(4) muU/ml INS, metformin 10 microM and pioglitazone 1.5 microM, reversed the IR induced by TNF-alpha restoring biologic response to 100% of INS effect alone. Furthermore, comparable results were obtained with glucose utilization/oxidation experiments in the H-411 E cells using glucose U-14C, trapping 14CO2 release in a hyamine filter and extracting 14C labelled lipids with Dole's reagent. In condusion, these data add scientific support for the use of both metformin and pioglitazone in treatment of IR in NIDDM patients and support a rationale for use of use of these drugs alone, and in conjuction with oral agents and/or INS treatment.

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