A 61-year-old man comes to the emergency department due to fever, chills, and a productive cough with thick, blood-tinged sputum for the past several days. His temperature is 38.8 C (102 F), blood pressure is 90/60 mm Hg, and pulse is 110/min. On examination, the patient is lethargic and ill appearing. Bronchial breath sounds and crackles are present in the right lung. Blood and sputum cultures grow Klebsiella pneumoniae. It is determined that the bacteria express a lipopolysaccharide on their outer membrane surface that stimulates toll-like receptors in the inflammatory cells. This in turn leads to degradation of the IκB inhibitor protein, which normally binds to a latent transcription factor found in the cytoplasm. Which of the following factors is most likely to be directly activated by the removal of this inhibitor protein?

Question

A 61-year-old man comes to the emergency department due to fever, chills, and a productive cough with thick, blood-tinged sputum for the past several days.  His temperature is 38.8 C (102 F), blood pressure is 90/60 mm Hg, and pulse is 110/min.  On examination, the patient is lethargic and ill appearing.  Bronchial breath sounds and crackles are present in the right lung.  Blood and sputum cultures grow Klebsiella pneumoniae.  It is determined that the bacteria express a lipopolysaccharide on their outer membrane surface that stimulates toll-like receptors in the inflammatory cells.  This in turn leads to degradation of the IκB inhibitor protein, which normally binds to a latent transcription factor found in the cytoplasm.  Which of the following factors is most likely to be directly activated by the removal of this inhibitor protein?

Quizplus · Accepted Answer

11ec160b_39f6_f560_9249_5fe2e4026f1e_MD0001_00 Nuclear factor-kappa B (NF-κB) is part of a family of transcription factors that perform a critical role in the immune response to infection and inflammation. In inflammatory cells, NF-κB is normally present in a latent, inactive state bound to its inhibitor protein, IκB. As part of the classical activation pathway, an extracellular signal, such as the binding of bacterial antigens to a toll-like receptor, causes activation of IκB kinase. This results in ubiquitination and subsequent destruction of IκB with the release of free NF-κB. Once free, NF-κB enters the nucleus and promotes the synthesis of a number of inflammatory proteins such as cytokines, acute phase reactants, cell adhesion molecules, and leukocyte-related growth factors. The inflammatory cascade is self-limiting as NF-κB also stimulates the transcription of more IκB, ultimately rebinding the freed NF-κB. (Choices A and E) Granulocyte colony-stimulating factor (G-CSF) is the principal protein that stimulates the production and release of neutrophils from the bone marrow. Tumor necrosis factor-α (TNF-α) plays a major role in the response to infection by increasing neutrophil chemotaxis and stimulating macrophage phagocytosis. Although NF-κB upregulates transcription of G-CSF and TNF-α, IκB degradation is not directly involved in the activation of these factors. (Choice B) Janus kinase 2 (JAK2) is a tyrosine kinase involved in the signaling pathway for myeloproliferation. Constituent activation of JAK2 is associated with polycythemia vera, essential thrombocytosis, and myelofibrosis. It does not play a major role in the immune response to infection. (Choice D) Although transforming growth factor-β (TGF-β) also has a role in the immune response and is triggered by inflammatory pathways, it is complexed to TGF-β binding protein and latency-associated peptide, not IκB. Educational objective: Nuclear factor-kappa B (NF-κB) is a transcription factor with a critical role in the immune response to infection. NF-κB is normally present in the cytoplasm in a latent, inactive state bound to its inhibitor protein, IκB. Extracellular substances such as lipopolysaccharide can initiate a signal cascade that results in the destruction of IκB and translocation of free NF-κB to the nucleus. __________ References: The nuclear factor NF-?B pathway in inflammation. (http://www.ncbi.nlm.nih.gov/pubmed/20457564) Regulation and function of NF-kappaB transcription factors in the immune system. (http://www.ncbi.nlm.nih.gov/pubmed/19302050)

A 61-Year-Old Man Comes to the Emergency Department Due to Fever