Systemic administration of the cytokine, TGF,f1, profoundly antagonized the development of polyarthritis in susceptible rats. TGF,81 administration (1 or 5 ,g/animal), initiated one day before an arthritogenic dose of streptococcal cell wall (SCW) fragments, virtually eliminated the joint swelling and distortion typically observed during both the acute phase (articular index, AI = 2.5 vs. 11; P < 0.025) and the chronic phase (Al = 0 vs. 12.5) of the disease. Moreover, TGF,61 suppressed the evolution of arthritis even when administration was begun after the acute phase ofthe disease. Histopathological examination of the joint revealed the systemic TGF,81 treatment greatly reduced inflammatory cell infiltration, pannus formation, and joint erosion. Consistent with the inhibition of inflammatory cell recruitment into the synovium, TGF,81 reversed the leukocytosis associated with the chronic phase of the arthritis. Control animals subjected to the same TGF,&1 dosing regimen displayed no discernable immunosuppressive or toxic effects even after 4 wk of treatment. These observations not only provide insight into the immunoregulatory effects of TGF#, but also implicate this cytokine as a potentially important therapeutic agent. (J. Clin.
The type II pneumocyte plays a principle role in the maintenance and repair of the pulmonary alveolar epithelium by increasing its rate of proliferation under conditions of epithelial damage. This investigation examined the role of the alveolar macrophage in the control of type II cell division through its ability to produce specific growth factors when activated in vitro. Type II cells were isolated from adult male rabbits and cultured in the presence of media and matrix that support cell proliferation. Proliferation was assessed by cell counting and pulsing with [3H]thymidine, followed by measurements of labeling index and TCA-insoluble radioactivity. Alveolar macrophages were cultured in serum-free media in the presence of a particulate stimulus. Conditioned media was diluted and added to type II cell cultures. Conditioned media from stimulated macrophage cultures was found to double basal type II cell proliferation, whereas media from unstimulated macrophage cultures had no effect. Macrophage production of type II cell growth-promoting activity was dependent on the concentration of the stimulus and the length of the incubation. Investigation into the identity of the growth-regulating protein established that it is heat labile, insensitive to reduction and acidic conditions, and sensitive to trypsin digestion. Its molecular weight appears to be greater than or equal to 25 kD. Addition of several characterized growth factors to type II cell cultures demonstrated that other known growth-promoting products of macrophages do not act as type II cell growth factors. The evidence presented suggests that in vitro activated alveolar macrophages produce a type II cell growth factor that may play a critical role in mediating repair of the alveolar epithelium.
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