Publications

Schistosomiasis (bilharzia) is a parasitic disease caused by several species of schistosome worms (blood flukes). The key pathogenic event in this disease is the formation of granulomas around schistosome eggs trapped in portal venules of the liver. Granulomas are a distinctive form of chronic inflammation characterized by localized aggregation of activated macrophages around an inciting stimulus. Each granuloma evolves to form a fibrous scar; in schistosomiasis, the result is widespread hepatic fibrosis and portal hypertension. To identify the specific immune signal molecules necessary for granuloma formation, we studied schistosome infections in severe combined immunodeficient (SCID) mice, which have normal macrophages but lack functional B or T lymphocytes. Here we report that the immunoregulatory cytokine tumour necrosis factor alpha is necessary and sufficient to reconstitute granuloma formation in schistosome-infected SCID mice. Moreover, we find that the parasitic worms require tumour necrosis factor alpha for egg-laying and for excretion of eggs from the host. The implication of this latter result is that the parasite has adapted so successfully to its host that it uses a host-derived immunoregulatory protein as a signal for replication and transmission.

BACKGROUND

Transforming growth factor-beta 1 (TGF-beta 1), a potent growth modulator produced by a variety of tumor cells, as well as by platelets, has pleiotropic effects on cell-extracellular matrix interactions and may influence tumor cell invasion and metastasis.

PURPOSE

Our purpose was to characterize the effects of TGF-beta 1 on the adhesion, motility, and invasiveness of a metastatic human pulmonary carcinoma (A549 cell line) in vitro.

METHODS

A549 cells were seeded onto type I collagen gels, and invasion over a 9-day period was measured in the presence or absence of TGF-beta 1 (0.1-10 ng/mL). In addition, cell adhesion to substrata coated with type I collagen (1-100 nM) as well as haptotactic migration through filters coated with type I collagen (100 micrograms/mL) were measured following a 24-hour treatment with TGF-beta 1 (1-10 ng/mL).

RESULTS

TGF-beta 1 stimulated the invasion of A549 cells into type I collagen gels in a dose-dependent manner. Both the number of cells entering the gel and the depth of invasion into the gel were increased. In addition, the effects of TGF-beta 1 were blocked in a dose-dependent manner by a purified polyclonal IgG against TGF-beta 1 but not by normal rabbit IgG. A549 cell invasion was accompanied by dramatic changes in A549 cell morphology that included the appearance of numerous long pseudopodia, consistent with a change in the motile behavior of these cells. TGF-beta 1 stimulated by approximately fourfold the haptotactic migration of A549 cells on polycarbonate filters coated with type I collagen. The TGF-beta 1-mediated increase in invasion and motility was accompanied by a fourfold increase in A549 cell adhesion to type I collagen.

CONCLUSIONS

The results suggest that TGF-beta 1 can influence cellular recognition of extracellular matrix components and can modulate cellular adhesion and migration on these components, leading to increased invasive potential.

IMPLICATIONS

Given the wide-spread tissue distribution of TGF-beta 1 and its secretion by a variety of tumor cells as well as by platelets, TGF-beta 1 may be an important autocrineparacrine regulator of the invasive phenotype in vivo.