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Kupffer cells induce liver progenitor cell proliferation in response to CDE diet-induced liver injury

Elsegood, C., Olynyk, J. and Yeoh, G. (2012) Kupffer cells induce liver progenitor cell proliferation in response to CDE diet-induced liver injury. In: Australian Gastroenterology Week 2012, 16 - 19 October 2012, Adelaide Convention Centre, S.A.


Background We have previously shown that both resident Kupffer cell and infiltrating monocyte-derived macrophage numbers increase in the liver in response to injury induced by the CDE diet.(1) The Kupffer cells and infiltrating macrophages are located adjacent to the portal veins as early as two days after the mice are placed on the diet. As the increase in macrophage numbers precedes the increase in liver progenitor cell numbers and macrophages express the LPC mitogens, TNF and TWEAK, we hypothesised that macrophages contribute to LPC proliferation. Aims To investigate the role of Kupffer cells in liver progenitor cell proliferation in response to CDE diet-induced liver injury. Methods We examined the role of Kupffer cells in CDE diet-induced liver injury and LPC proliferation using clodronate liposomes to ablate Kupffer cells but not blood monocytes. Results We found that Kupffer cells were required for the induction of LPC proliferation in response to CDE diet-induced injury, as the number of LPCs did not increase in response to CDE diet-induced injury when the Kupffer cells were depleted either before or after the induction of injury. Importantly, clodronate liposomes were not directly toxic to LPCs in vitro. Kupffer cell depletion resulted in a reduction in expression of TNF, IL-6, and HGF, but not TWEAK, at the mRNA level in the liver. Kupffer cell depletion also delayed the recruitment of monocytes to the liver. Further, Kupffer cell depletion did not affect liver damage, as judged by serum ALT levels, suggesting that the reduction in LPC numbers was not a result of reduced liver damage. This study also showed that the Kupffer cells did not appear to play a role in the recruitment of other immune cells, such as T and B lymphocytes, which may also provide LPC proliferative cytokines. Conclusion Our data indicates that Kupffer cells induce LPC proliferation as a result of infl uencing LPC proliferative cytokine production. Reference 1. Viebahn, C. S., V. Benseler, L. E. Holz, C. L. Elsegood, M. Vo, P. Bertolino, R. Ganss, and G. C. Yeoh. 2010. Invading macrophages play a major role in the liver progenitor cell response to chronic liver injury. Journal of Hepatology 53:500–507.

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