Role of mRNA stabilizing proteins during macrophage polarization and implications for tumor development

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Conditioned medium (CM) of apoptotic cells polarizes macrophages (Mφ) towards an antiinflammatory and pro-angiogenic phenotype, which shares a number of characteristics with M2-type Mφ and/or tumor associated Mφ (TAMs). Having proven that CM activates HuR (embryonic lethal abnormal vision (ELAV)-like family member) and in turn causes cyclooxygenase-2 (Cox-2) expression, we hypothesize that global changes in the cytokine profile of polarized Mφ are under the control of mRNA binding proteins (RBPs). We follow expression and activity changes of HuR, TTP (tristetraprolin) and AUF-1 in response to CM and correlate their alterations to established M2/TAM-markers as well as functional consequences of polarized Mφ to elicit pro-angiogenic responses such as proliferation, sprouting and vessel formation. Knockdown of RBPs will establish a cause-effect relation and RNA-immunoprecipitation using the RBPs followed by gene arrays will be used to identify novel targets of RBPs that contribute to a tumor supporting phenotype of Mφ in response to CM. Using the technology of adoptive gene transfer it is our intention to show a functional consequence of macrophages with a knockdown of either HuR, TTP or AUF-1 towards tumor progression in vivo. We anticipate that our study will add to the understanding how RBPs contribute to Mφ polarization in response to CM, thereby creating a tumor promoting microenvironment.