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The acute phase response is a systemic reaction to infection or injury mediated by pro-inflammatory cytokines (IL-6, TNF-α, IL-1). It includes fever (hypothalamic resetting by PGE2), increased hepatic synthesis of acute phase proteins (CRP, SAA, fibrinogen), anorexia, lethargy, and metabolic changes. While initially protective (iron sequestration limits bacterial growth, fever enhances immune response), prolonged activation causes cachexia, insulin resistance, and multi-organ dysfunction in sepsis.
Understand the cytokine cascade triggering fever and hepatic protein synthesis. Study acute phase proteins as biomarkers of inflammation. Consider how anti-inflammatory therapy (NSAIDs, antipyretics) may be beneficial or harmful depending on severity.
Fever is not harmful—it is an adaptive response that enhances immune function. The acute phase response is not synonymous with SIRS; SIRS is a broader systemic inflammatory state that can be triggered by non-infectious triggers (trauma, burns).
You already know from acute inflammation that local tissue injury triggers a cascade: mast cells degranulate, macrophages release cytokines, neutrophils flood the site, and blood vessels dilate and become leaky. That local response is contained — the redness and swelling stay near the injury. The acute phase response is what happens when the same cytokine signals escape the local compartment and reach the circulation. IL-6, TNF-α, and IL-1β, which you studied as mediators of local inflammation, act as messengers that broadcast the alarm system-wide.
The most immediate systemic effect is fever. IL-1 and TNF-α act on the hypothalamus, inducing production of prostaglandin E2 (PGE2), which raises the thermostat set-point. This is an evolved defense: most pathogens replicate less efficiently at 38–39°C, while many immune processes — including neutrophil migration and T-cell activation — are enhanced. The sensation of feeling cold at the onset of fever (rigors, shivering) reflects the body generating heat to reach the new, elevated set-point. NSAIDs work by blocking prostaglandin synthesis, which explains both their antipyretic and anti-inflammatory effects.
Simultaneously, IL-6 drives a dramatic reprogramming of liver protein synthesis called the acute phase protein response. The liver downregulates "negative" acute phase proteins (albumin, transferrin) and massively upregulates "positive" ones: C-reactive protein (CRP), serum amyloid A, fibrinogen, and complement components. CRP — which can rise 1,000-fold during acute inflammation — opsonizes bacteria and activates complement, directly supporting pathogen clearance. Fibrinogen elevation helps wall off infection through clot formation. Transferrin downregulation sequesters iron away from bacteria, which require iron for growth — a form of nutritional immunity. These responses look wasteful from a metabolic standpoint but make sense as an integrated defensive strategy.
The systemic metabolic changes — anorexia, lethargy, muscle catabolism, insulin resistance — are also cytokine-mediated and reflect resource reallocation. Skeletal muscle is broken down to supply amino acids for hepatic protein synthesis. Anorexia reduces foraging behavior (which would expose a sick animal to predation). Lethargy conserves energy for the immune response. Taken together, the acute phase response is the body running a coordinated emergency program. Its danger is chronicity: in sepsis, unresolved infection sustains cytokine drive, leading to prolonged muscle wasting, organ hypoperfusion, and eventually the multi-organ dysfunction syndrome you will study next.