Considering the critical role macrophages play in SIV infections, and the threat that H1N1pdm could further evolve higher virulence in pigs and subsequently infect humans, we were interested in profiling host responses of swine macrophages to H1N1pdm, and more importantly, in exploring the underlying mechanism of host response regulation including antiviral, proinflammatory responses, and apoptosis in pigs. In this report, we will demonstrate that swine macrophages are susceptible to infection by H1N1pdm. We will show a unique pattern of proinflammatory cytokine responses to the infection, which are distinctly regulated by swine mitogen-activated protein (MAP) kinases. We have also observed cross-talk between MAP kinase and NFkB pathways, and our data indicate that MAP kinase ERK1/2 and JNK1/2 may impact the activation of NFkB through the induction of RIG-1, leading to IFN-b induction in H1N1pdm-infected swine macrophages.