Acute Phase Inflammatory Proteins

Clinical Background

Plasma proteins termed acute phase inflammatory proteins or reactants are involved in the innate system’s response to inflammation, tissue injury or malignancy. During the inflammatory process, the plasma concentration of these acute phase proteins increases or decreases by at least 50%.

Alpha-1-acid glycoprotein

Produced by hepatocytes into the blood in response to physical trauma, infection, wounding
Regulated - by proinflammatory cytokines that include interleukin 1 (IL-1), interleukin 6 (IL-6), chemokines (IL-8) and glucocorticoids
Stimulates immunomodulatory activity that may reduce collateral damage caused by inflammation

Cytokines

Cytokines are integrally involved in inflammatory reactions
Interleukins are cytokines that act as mediators between leukocytes. There are 18 identified interleukins with varying effects

Human Plasma Acute Phase Proteins
Positive Acute Phase Proteins
Complement system	C3, C4, C9, Factor B, C1 inhibitor, C4b-BP, Mannose-BP
Coagulation system	Fibrinogen, Plasminogen, Urokinase, Protein S, Vitronectin, PAI-1
Antiproteases	Alpha 1-Protease inhibitor, alpha-1-antichymotrypsin, Pancreatic secretory trypsin inhibitor, Inter-alpha-trypsin inhibitor
Binding Proteins	Ceruloplasmin, Haptoglobin, Hemopexin, LPS-BP
Proteins involved in inflammatory response	Secreted phospholipase A2, IL-IRA, GM-CSF
Others	Serum amyloid A, C-reactive protein, ACP, Fibronectin, Ferritin, Angiotensinogen
Negative Acute Phase Proteins
Albumin, Transferrin, alpha 2-HS-Glycoprotein, alpha-fetoprotein, Thyroxine-BP, IGF-1,Factor XII
(Used with permission from Ceciliani, 2007, 91)

Tumor necrosis factor (TNF-alpha, cachectin)

Produced by mononuclear phagocytes
In vitro activities attributed to TNF-alpha
- Activation of T-cells
- Pyrogenicity and endotoxemia
- Mitogenic effects on fibroblasts
- Resorption of bone and cartilage
- Activation of neutrophil function
- Decreased activity of several enzymes involved in lipid metabolism
- Decreased synthesis of hepatic protein
- Cachexia
- Induction of
  - Interleukin-6 (IL-6), Interleukin-1 (IL-1) and Interleukin-2 (IL-2) receptors
  - Granulocyte monocyte-colony stimulating factor (GM-CSF)
  - C-myc and c-fos genes
  - Epidermal growth factor (EGF)

Cytokines

Interleukin-6
- A glycoprotein produced by activated T-cells
- Involved in B-cell differentiation into plasma cells
  - Usually not detected in normal serum, plasma, cerebral spinal fluid (CSF) or joint fluid
- Elevated levels occur in
  - Inflammatory processes
    - Infections (endotoxemia)
    - Collagen vascular diseases
  - Alcoholic cirrhosis
  - Chronic renal failure
  - Central nervous system inflammation (increased CSF levels)
    - Bacterial meningitis
    - Central nervous system (CNS) involvement in systemic lupus erythematosus
  - Rheumatoid arthritis (increased synovial fluid levels)
Interleukin-2
- A glycoprotein produced by activated T-cells
- Also known as:
  - T-cell growth factor
  - Thymocyte simulation factor (TSF)
  - Thymocyte mitogenesis factor (TMF)
  - T-cell replacing factor (TRF)
  - Killer-helper factor (KHF)
- Most notable immunologic function is the activation, proliferation and promotion of:
  - T-cells
  - B-cells
  - Natural killer cells (NK cells)
- Decreased IL-2 production associated with:
  - Systemic lupus erythematosus (SLE)
  - Hodgkin lymphoma
  - Lepromatous leprosy
  - AIDS
  - Common variable hypogammaglobulinemia
  - Chronic mucocutaneous candidiasis

Interleukin-1-beta

Produced by activated macrophages
Mediates a wide variety of biological actions
- Stimulates expression of IL-2 receptors
- Stimulates production and secretion of IL-2
In synergy with tumor necrosis factor alpha, elevated interleukin-1-beta is seen in:
- Septic shock
- Cerebrospinal fluid
  - Meningitis
  - Multiple sclerosis

Interleukin-8

Produced by activated macrophages
Pro-inflammatory cytokine and chemoattractant for neutrophils
Elevated levels observed in many inflammatory processes, including infections and connective tissue diseases

See Also

Cardiovascular Disease (Non-traditional Risk Markers) - Risk Markers - CVD (Non-traditional)

Proteins

Sepsis in Newborns - C-Reactive Protein

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: Alpha-1-Acid Glycoprotein, Serum

ARUP #: 0050002

Methodology: Nephelometry

Use:

Monitor acute phase reactions such as inflammatory conditions, rheumatoid arthritis and malignant neoplasms

Limitations:

Limited clinical use

Follow-up:

Test name: Tumor Necrosis Factor - alpha

ARUP #: 0051539

Methodology: Multi-Analyte Fluorescence Detection

Use:

Elevated levels seen in
- Septic shock
- Meningitis and other central nervous system processes such as multiple sclerosis

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Test name: Interleukin 6 by Chemiluminescence

ARUP #: 0050489

Methodology: Chemiluminescent Immunoassay

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Test name: Cytokine Panel 12 by MAFD

ARUP #: 0051394

Methodology: Multi-Analyte Fluorescent Detection

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Test name: Cytokine Panel, Monokines by MAFD

ARUP #: 0051524

Methodology: Multi-Analyte Fluorescence Detection

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Test name: Interleukin 1 beta by MAFD

ARUP #: 0051536

Methodology: Multi-Analyte Fluorescence Detection

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Test name: Interleukin 2 Receptor by MAFD

ARUP #: 0051529

Methodology: Multi-Analyte Fluorescence Detection

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Test name: Interleukin 6 by MAFD

ARUP #: 0051537

Methodology: Multi-Analyte Fluorescence Detection

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Test name: Interleukin 8 by MAFD

ARUP #: 0051538

Methodology: Multi-Analyte Fluorescence Detection

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Test name: Interleukin 1 Beta by Chemiluminescence

ARUP #: 0050494

Methodology: Chemiluminescent Immunoassay

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Test name: Interleukin 2 by ELISA

ARUP #: 0099230

Methodology: Enzyme-Linked Immunosorbent Assay

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Test name: Interleukin 2 Receptor by Chemiluminescence

ARUP #: 0050502

Methodology: Chemiluminescent Immunoassay

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Test name: Interleukin 8 by Chemiluminescence

ARUP #: 0050490

Methodology: Chemiluminescent Immunoassay

Use:

Use for research purposes or for understanding the pathophysiology of immune, infectious or inflammatory disorders

Additional Tests Available

Test name: Cytokine Panel, TH1 by MAFD

ARUP #: 0051408

Methodology: Multi-Analyte Fluorescent Detection

Comments:

Test name: Cytokine Panel, TH2 by MAFD

ARUP #: 0051518

Methodology: Multi-Analyte Fluorescence Detection

Comments:

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, 12 Cytokines

ARUP #: 0051540

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interferon gamma

ARUP #: 0051574

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 1 beta

ARUP #: 0051580

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 2

ARUP #: 0051571

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 2 Receptor

ARUP #: 0051572

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 4

ARUP #: 0051576

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 5

ARUP #: 0051577

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 6

ARUP #: 0051581

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 8

ARUP #: 0051582

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Alpha-1-Antitrypsin

ARUP #: 0050001

Methodology: Immunoturbidimetric

Comments:

Test name: Cytokine Panel 12 by MAFD

ARUP #: 0051394

Methodology: Multi-Analyte Fluorescent Detection

Comments:

Test name: Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, 12 Cytokines

ARUP #: 0051584

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, TH1 Cytokines

ARUP #: 0051558

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, TH2 Cytokines

ARUP #: 0051562

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, TH2 Cytokines

ARUP #: 0051586

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Interleukin 1 Beta by Chemiluminescence

ARUP #: 0050494

Methodology: Chemiluminescent Immunoassay

Comments:

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Monokines

ARUP #: 0051566

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Cytokine Panel, TH1 by MAFD

ARUP #: 0051408

Methodology: Multi-Analyte Fluorescent Detection

Comments:

Test name: Cytokine Panel, Monokines by MAFD

ARUP #: 0051524

Methodology: Multi-Analyte Fluorescence Detection

Comments:

Test name: Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, TH1 Cytokines

ARUP #: 0051585

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, Monokines

ARUP #: 0051587

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Interleukin-1-Receptor-Associated Kinase-4 (IRAK-4) Deficiency Screen

ARUP #: 0051393

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies

ARUP #: 0095899

Methodology: Flow Cytometry

Comments:

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 8

ARUP #: 0051582

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Tumor Necrosis Factor alpha

ARUP #: 0051583

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

Test name: Cytokine Production by Mononuclear Cells in Response to Mitogen Stimulation, Interleukin 12

ARUP #: 0051573

Methodology: Cell Culture/Multi-Analyte Fluorescence Detection

Comments:

References

Cited References

Ceciliani F, Pocacqua V. The acute phase protein alpha1-acid glycoprotein: a model for altered glycosylation during diseases. Curr Protein Pept Sci. 2007;8(1):91-108.

General References

Atkins MB. Interleukin-2: clinical applications. Semin Oncol. 2002;29(3 Suppl 7):12-17.

Becknell B, Caligiuri MA. Interleukin-2, interleukin-15, and their roles in human natural killer cells. Adv Immunol. 2005;86:209-239.

Gaffen SL, Liu KD. Overview of interleukin-2 function, production and clinical applications. Cytokine. 2004;28(3):109-123.

Kishimoto T. Interleukin-6: from basic science to medicine--40 years in immunology. Annu Rev Immunol. 2005;23:1-21.

Remick DG. Interleukin-8. Crit Care Med. 2005;33(12 Suppl):S466-S467.

Song M, Kellum JA. Interleukin-6. Crit Care Med. 2005;33(12 Suppl):S463-S465.

Younes A, Aggarwall BB. Clinical implications of the tumor necrosis factor family in benign and malignant hematologic disorders. Cancer. 2003;98(3):458-467.

References from the ARUP Institute for Clinical and Experimental Pathology Research®

La Pine TR, Joyner JL, Augustine NH, Kwak SD, Hill HR. Defective production of IL-18 and IL-12 by cord blood mononuclear cells influences the T helper-1 interferon gamma response to group B Streptococci. Pediatr Res. 2003;54(2):276-281.

Martins TB, Pasi BM, Litwin CM, Hill HR. Heterophile antibody interference in a multiplexed fluorescent microsphere immunoassay for quantitation of cytokines in human serum. Clin Diagn Lab Immunol. 2004;11(2):325-329.

Martins TB, Pasi BM, Pickering JW, Jaskowski TD, Litwin CM, Hill HR. Determination of cytokine responses using a multiplexed fluorescent microsphere immunoassay. Am J Clin Pathol. 2002;118(3):346-353.

Medical Reviewers

Hill, Harry R., M.D. Group Medical Director, Laboratory of Immunology, ARUP Laboratories, and Executive Director of the ARUP Institute for Clinical and Experimental Pathology; Professor and Division Head, Clinical Pathology, University of Utah

Litwin, Christine, M.D. Medical Director, Immunology at ARUP Laboratories; Professor, Clinical Pathology, University of Utah

Comprehensive Review: July 2008
Last Update: July 2008