TGFβ1 Modulation of Inflammation in Premalignant Squamous Lesions is IL-17-dependent and Independent (95.5)

Abstract

Abstract The proinflammatory functions of TGFβ1 are dependent on the local cytokine milieu. Overexpression of TGFβ1 in epidermis provokes an inflammatory response in the skin while its role in skin tumors is still not clear. To evaluate the effects of TGFβ1 in modulating inflammatory cytokine production, we overexpressed TGFβ1 in premalignant primary keratinocytes derived from an inducible TGFβ1 transgenic mouse. TGFβ1 induced expression of TNFα, IL-1β and IL-23a in vitro and conditioned media from these cells polarized naïve T cells to a Th17 phenotype that was dependent on TGFβ1 signaling. Overexpression of TGFβ1 in premalignant squamous lesions resulted in an increase in IL-17 production by CD4+ and γδ+ T cells as well as rapid regression of the tumors. Microarray analysis of gene expression following induction of TGFβ1 in premalignant skin tumors indicated a significant upregulation of proinflammatory genes at day 2. This was followed by an increase in MPO+, F4/80+ and CD8+ cells in the tumors and increase in CD8+ effectors and IFNγ+ cells in the skin draining lymph nodes at day 5. Concomitantly, the percentage of tumor CD11b+Ly6G+ cells was reduced in TGFβ1 overexpressing tumors. Neutralization of IL-17 blocked TGFβ1 induced CD11b+Ly6g- macrophage infiltration in the tumor but did not alter the reduction of CD11b+Ly6g+ cells or tumor regression. Thus, TGFβ1 overexpression causes IL-17 dependent and independent changes in the premalignant tumor inflammatory microenvironment.